KR20200027992A - Antagonist of muscarinic acetylcholine receptor M4 - Google Patents

Abstract

Disclosed herein are cyclopropylpiperidine compounds that may be useful as antagonists of the muscarinic acetylcholine receptor M ₄ (mAChR M ₄ ). Also disclosed herein are methods of making compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and compositions.

Description

Antagonist of muscarinic acetylcholine receptor M4

relation Cross reference to the filing

This application claims priority to U.S. Provisional Application No. 62 / 531,818, filed on July 12, 2017, the entirety of which is incorporated herein by reference.

Technical field

The present disclosure relates to compounds, compositions and methods for treating disorders associated with muscarinic acetylcholine receptor dysfunction.

Parkinson's disease (PD) is the second most common neurodegenerative disease with increasing prevalence as a function of age. Moreover, early onset PD is also increasing. PD is characterized by progressive degeneration and loss of dopaminergic neurons in the substantia nigra (SN) and basal ganglia (BG), which are pronounced motor symptoms including sinusitis, tremor, stiffness, gait dysfunction and postural instability. Causes Currently, levodopa (L-DOPA) is a standard treatment for treating motor symptoms, but it is not curative, and prolonged use can cause L-DOPA induced dyskinesia (LID). .

Prior to L-DOPA, compounds with anticholinergic activity have shown the preferred mode of PD treatment. Cholinergic neurons provide important neuromodulatory control of the BG motor circuit. Although the action of the cholinergic pathway on the basal nuclear pathway is complex, activation of the muscarinic acetylcholine receptor (mAChR) generally has an action against dopamine (DA) signaling. For example, mAChR agonists inhibit DA release and inhibit multiple behavioral effects of drugs that increase DA levels and signaling. Interestingly, the muscarinic acetylcholine receptor (mAChR) antagonist is the first available treatment for PD and is still widely used for the treatment of this disorder. Although many studies of the action of mAChR antagonists have been conducted prior to the introduction of randomized controlled trials, recent well-controlled double-blind crossover design studies have demonstrated significant improvements in many aspects of motor function in patients receiving mAChR antagonists. do. Unfortunately, mAChR antagonists have a number of dose limiting side effects that severely limit their clinical usefulness, including a number of peripheral side effects, and confusion and severe cognitive impairment.

Since side effects associated with mAChR antagonists limit the tolerable dose, previous clinical studies have been achieved when the dose of mAChR antagonists is increased to achieve a more complete blockade of specific mAChR subtypes responsible for the anti-Parkinson's disease effect of these substances You can get too little efficiency. mAChR includes five subtypes called M ₁ to M ₅ . Available mAChR antagonists such as scopolamine are non-selective across these subtypes, and many of these side effects are probably mediated by mAChR subtypes that are not involved in antiparkinsonism activity. Thus, compounds that have a more selective profile for individual mAChRs may provide advantages in PD, and related disorders such as dystonia. For example, some studies may indicate that the M ₄ mAChR subtype may play a major role in mAChR regulation of basal nuclear motor function.

For the treatment of disorders such as neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction in a compound, a pharmaceutical composition comprising the compound, a method for preparing the compound, a kit comprising the compound, and a mammal Methods of using compounds, compositions and kits are disclosed.

In one aspect, the compound of Formula I:

[Formula I]

Or a pharmaceutically acceptable salt thereof; here

A is a 5 or 6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 9 to 10 membered fused bisyl having 1 to 4 nitrogen atoms. Is a click heteroaryl ring system, wherein A is optionally substituted with 1 to 4 substituents independently selected from halo, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl;

Q is selected from NR ^a , O and CR ^b R ^c ;

R ¹ is hydrogen, halo, -OR ^d , -N (R ^d ) ₂ , C ₁ -C ₄ alkyl, -CH = CH-C ₁ -C ₄ alkyl, optionally substituted cycloalkyl, optionally substituted cyclo Alkenyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl and -CH = CH-G;

G is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycle, an optionally substituted aryl or an optionally substituted heteroaryl;

R ² and R ³ are independently selected from hydrogen, C ₁ -C ₄ alkyl and halo, or R ² and R ³ are taken together to form an oxo group;

Each R ⁴ is independently selected from halo, C ₁ -C ₄ alkyl and -OR ^e ;

R ⁵ and R ⁶ are independently selected from hydrogen, C ₁ -C ₈ alkyl and-(CR ^f R ^g ) _n -Y ¹ ;

Each Y ¹ is independently selected from an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycle, an optionally substituted aryl and an optionally substituted heteroaryl;

Each R ^a , R ^b , R ^c , R ^d , R ^e , R ^f and R ^g is independently selected from hydrogen, C ₁ -C ₄ alkyl and aryl;

m is 0, 1 or 2;

n is 0, 1 or 2.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect, the invention provides a method of antagonizing mAChR M ₄ in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or composition thereof.

In another aspect, the invention provides a method of treating a disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or composition thereof, wherein the subject Will benefit from the antagonism of mAChR M ₄ .

In another aspect, the invention provides a method of treating a motor condition in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or composition thereof.

In another aspect, the invention provides a kit comprising a compound of Formula I, or a pharmaceutically acceptable salt or composition thereof, and instructions for use.

In yet another embodiment the present invention provides a mAChR M for use of ₄ antagonize, mAChR M ₄ for the treatment of a disorder that is alleviated by antagonism, or for the treatment of motor symptoms, the compounds of formula I, or a pharmaceutically Provides a scientifically acceptable salt or composition.

In yet another embodiment the present invention provides a compound of mAChR M, mAChR M for antagonist to ₄₄ in the manufacture of a medicament for the treatment of, or motor symptoms for the treatment of a disorder that is alleviated by antagonism of the formula I, or Provides the use of a pharmaceutically acceptable salt or composition thereof.

1 shows the structure of compound O (Example 5) obtained by X-ray crystallographic analysis.

Disclosed herein are compounds that are antagonists of the muscarinic acetylcholine receptor M ₄ (mAChR M ₄ ), methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and pharmaceutical compositions do. Compounds include functionalized cyclopropylpiperidine compounds.

1. Definition

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods and examples disclosed herein are illustrative only and are not intended to be limiting.

The terms "include", "include", "having", "having", "can do", "contain" and derivatives thereof as used herein are open type that do not exclude the possibility of additional actions or structures. It is intended to be a transitional phrase, term or word. The singular forms "a", "an" and "the" include plural references unless the context clearly indicates otherwise. This specification also contemplates other embodiments, whether expressly described or not, the embodiments or elements "comprising of", "consisting of" and "consisting essentially of" as presented herein.

The modifier “about” used in connection with a quantity includes the specified value and has a meaning determined by the context (eg, at least includes a degree of error related to measurement of a specific quantity). The modifier "about" should also be considered to disclose a range defined by the absolute values of both endpoints. For example, the expression "about 2 to about 4" also discloses the range "2 to 4". The term “about” can refer to ± 10% of the indicated number. For example, "about 10%" may represent a range of 9% to 11%, and "about 1" may mean 0.9 to 1.1. Other meanings of "about" may be apparent from the context, such as rounding, so that, for example, "about 1" may mean from 0.5 to 1.4.

Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this specification, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed., Inner cover, and specific functional groups are generally defined as described therein . Additionally, the general principles of organic chemistry as well as specific functional moieties and reactivity are described in Organic Chemistry , Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry , 5 ^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations , VCH Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis , 3 ^rd Edition, Cambridge University Press, Cambridge, 1987; The entire contents of each of these are incorporated herein by reference.

The term “alkoxy” as used herein refers to an alkyl group as defined herein attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

The term "alkyl" as used herein means a straight or branched chain saturated hydrocarbon containing 1 to 10 carbon atoms. The term “lower alkyl” or “C ₁ -C ₆ -alkyl” means a straight or branched chain hydrocarbon containing 1 to 6 carbon atoms. The term "C ₁ -C ₃ -alkyl" means a straight or branched chain hydrocarbon containing 1 to 3 carbon atoms. Representative examples of alkyl are methyl, ethyl, n -propyl, iso -propyl, n -butyl, sec -butyl, iso -butyl, tert -butyl, n -pentyl, isopentyl, neopentyl, n- hexyl, 3-methyl Hexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 4,4-dimethylpentan-2-yl, n -heptyl, n -octyl, n -nonyl and n -decyl. Does not.

The term "alkenyl" as used herein means a straight or branched chain hydrocarbon containing at least one carbon-carbon double bond and 2 to 10 carbon atoms.

The term “alkoxyalkyl” as used herein refers to an alkoxy group as defined herein, attached to the parent molecular moiety through an alkyl group as defined herein.

The term “alkoxyfluoroalkyl” as used herein refers to an alkoxy group as defined herein attached to the parent molecular moiety through a fluoroalkyl group as defined herein.

The term "alkylene" as used herein refers to a divalent group derived from a straight or branched chain hydrocarbon of 1 to 10 carbon atoms, for example 2 to 5 carbon atoms. Representative examples of alkylene are -CH ₂ CH _2- , -CH ₂ CH ₂ CH _2- , -CH ₂ CH (CH ₃ ) CH _2- , -CH ₂ CH ₂ CH ₂ CH _2- , -CH ₂ CH ( CH ₃ ) CH ₂ CH ₂ -and -CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -are included, but are not limited thereto.

The term “alkylamino” as used herein means that at least one alkyl group as defined herein is attached to the parent molecular moiety through an amino group as defined herein.

The term "amide" as used herein means -C (O) NR- or -NRC (O)-, where R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl or Heteroalkyl.

The term “aminoalkyl” as used herein means that at least one amino group as defined herein is attached to the parent molecular moiety through an alkylene group as defined herein.

The term "amino" as used herein means -NR _x R _y , where R _x and R _y can be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkenyl or heteroalkyl. . In the case of an aminoalkyl group in which amino attaches two different moieties together, or in the case of any other moiety, amino may be -NR _x- , where R _x is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle , Alkenyl or heteroalkyl.

The term "aryl" as used herein refers to a phenyl group or a bicyclic fused ring system. The bicyclic fused ring system is attached to a parent molecular moiety and fused to a cycloalkyl group, phenyl group, heteroaryl group as defined herein, or heterocycle as defined herein, attached to the parent molecular moiety. It is illustrated by a phenyl group. Representative examples of aryl include, but are not limited to, indol-4-yl, naphthyl, phenyl, benzodioxol-5-yl and tetrahydroquinolin-6-yl.

The term "cyanoalkyl" as used herein means that at least one -CN group is attached to the parent molecular moiety through an alkylene group as defined herein.

The term "cyanofluoroalkyl" as used herein means that at least one -CN group is attached to the parent molecular moiety through a fluoroalkyl group as defined herein.

The term "cycloalkoxy" as used herein refers to a cycloalkyl group as defined herein, attached to a parent molecular moiety through an oxygen atom.

The term "cycloalkyl" as used herein refers to a carbocyclic ring system containing 3 to 10 carbon atoms, 0 heteroatoms and 0 double bonds. Cycloalkyl can be monocyclic, bicyclic, bridged, fused or spirocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl and bicyclo [1.1.1] pentanyl. Does not. “Cycloalkyl” also means that a cycloalkyl group is attached to a parent molecular moiety and an aryl group (eg, phenyl group) as defined herein, a heteroaryl group as defined herein, or a heterocycle as defined herein. It contains a carbocyclic ring system fused to. Representative examples of such cycloalkyl groups are 2,3-dihydro-1H-indenyl (eg, 2,3-dihydro-1H-inden-1-yl and 2,3-dihydro-1H-indene-2 -Yl), 6,7-dihydro-5H-cyclopenta [b] pyridinyl (eg, 6,7-dihydro-5H-cyclopenta [b] pyridin-6-yl), oxaspiro [3.3 ] Heptanyl (eg, 2-oxaspiro [3.3] heptan-6-yl) and 5,6,7,8-tetrahydroquinolinyl (eg, 5,6,7,8-tetrahydro) Quinolin-5-yl).

The term “cycloalkenyl” as used herein contains at least one carbon-carbon double bond, preferably non-aromatic monocyclic or multicyclic (5 to 10 carbon atoms per ring) For example, a bridged) ring system. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl. An exemplary bridged bicyclic ring system is bicyclo [2.2.1] hept-2-enyl.

The term “fluoroalkyl” as used herein refers to an alkyl group as defined herein wherein 1, 2, 3, 4, 5, 6, 7 or 8 hydrogen atoms have been replaced by fluorine. Means Representative examples of fluoroalkyl include 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl and 3,3,3-trifluoropropyl. The same trifluoropropyl is included, but is not limited thereto.

The term "fluoroalkoxy" as used herein means that at least one fluoroalkyl group as defined herein is attached to the parent molecular moiety through an oxygen atom. Representative examples of fluoroalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy and 2,2,2-trifluoroethoxy.

The term "halogen" or "halo" as used herein means Cl, Br, I or F.

The term “haloalkyl” as used herein refers to an alkyl group as defined herein wherein 1, 2, 3, 4, 5, 6, 7 or 8 hydrogen atoms have been replaced by halogen. it means.

The term “haloalkoxy” as used herein means that at least one haloalkyl group as defined herein is attached to the parent molecular moiety through an oxygen atom.

The term "halocycloalkyl" as used herein means a cycloalkyl group as defined herein, wherein one or more hydrogen atoms have been replaced by halogen.

The term "heteroalkyl" as used herein means an alkyl group as defined herein, wherein one or more carbon atoms have been replaced with a heteroatom selected from S, O, P and N. Representative examples of heteroalkyl include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, amides and alkyl sulfides.

The term “heteroaryl” as used herein refers to an aromatic monocyclic ring or aromatic bicyclic ring system. The aromatic monocyclic ring is at least one heteroatom independently selected from the group consisting of N, O and S (e.g. 1, 2, 3 or 4 independently selected from O, S and N) Heteroatoms). The 5-membered aromatic monocyclic ring has 2 double bonds, and the 6-membered 6-membered aromatic monocyclic ring has 3 double bonds. Bicyclic heteroaryl groups are attached to the parent molecular moiety, monocyclic cycloalkyl groups as defined herein, monocyclic aryl groups as defined herein, monocyclic heteroaryl groups as defined herein, or , Exemplified by a monocyclic heteroaryl ring fused to a monocyclic heterocycle as defined herein. Representative examples of heteroaryl include indolyl, pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, benzo Pyrazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadia Zolyl, imidazolyl, thiazolyl, isothiazolyl, thienyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzooxadiazolyl, benzothienyl, benzofuranyl, isobenzofuranyl, furanyl, Oxazolyl, isooxazolyl, furinyl, isoindoleyl, quinoxalinyl, indazolyl, quinazolinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, isoquinolinyl, quinolinyl Neil, 6,7-dihydro-1,3-benzothiazolyl, imidazo [1,2-a] pyridinyl, naphthyridinyl, pyridoimidazolyl, thiazolo [5,4-b] pyridine- 2-yl, thiazolo [5,4-d] pyrimidin-2-yl, [1,2,4] triazolo [4,3-b] pyridazinyl, Microporous crude [1,2-b] pyridazinyl, include, but possess phthalazine, but is not limited to this.

The term “heterocycle” or “heterocyclic” as used herein means a monocyclic heterocycle, bicyclic heterocycle or tricyclic heterocycle. Monocyclic heterocycles are 3-, 4-, 5-, 6-, 7- or 8-membered rings containing at least one heteroatom independently selected from the group consisting of O, N and S. The ternary or quaternary ring contains 0 or 1 double bonds and one heteroatom selected from the group consisting of O, N and S. The 5-membered ring contains 0 or 1 double bond and 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S. The 6-membered ring contains 0, 1 or 2 double bonds and 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S. The 7- and 8-membered rings contain 0, 1, 2 or 3 double bonds and 1, 2 or 3 heteroatoms selected from the group consisting of O, N and S. Representative examples of monocyclic heterocycles are azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1, 3-dithianil, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isooxazolinyl, isooxazolidinyl, morpholinyl, 2-oxo-3-piperidinyl, 2 -Oxoazpan-3-yl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl, piperidinyl, pyranyl, pyra Jolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thia Ginanil, 1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxydothiomorpholinyl (thiomorpholine sulfone), thiopyranyl and tritianyl. Bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or between mono A monocyclic heterocycle fused to a click heterocycle, or a spiro heterocycle group, or an alkylene bridge of 1, 2, 3 or 4 carbon atoms of two nonadjacent atoms of the ring, or 2, 3 or It is a bridged monocyclic heterocycle ring system linked by an alkenylene bridge of 4 carbon atoms. Representative examples of bicyclic heterocycles include benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline, 2-azaspiro [3.3] heptan-2-yl, 2-oxa-6-azaspiro [3.3] heptan-6-yl, azabicyclo [2.2.1] heptyl (2-azabicyclo [2.2.1] Hept-2-yl), azabicyclo [3.1.0] hexanyl (including 3-azabicyclo [3.1.0] hexane-3-yl), 2,3-dihydro-1 H -indolyl, Isoindolinyl, octahydrocyclopenta [ c ] pyrroleyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. A tricyclic heterocycle is a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or between mono Bicyclic heterocycle fused to a click heterocycle, or an alkylene bridge of 2, 3, or 4 carbon atoms of two nonadjacent atoms in a bicyclic ring, or 2, 3, or 4 carbons Exemplified by bicyclic heterocycles linked by an alkenylene bridge of atoms. Examples of the tricyclic heterocycle include octahydro-2,5-epoxypentalene, hexahydro- 2H -2,5-methanocyclopenta [ b ] furan, hexahydro- 1H- 1,4-methano Cyclopenta [ c ] furan, aza-adamantane (1- ^azatricyclo [3.3.1.1 ^3,7 ] decane) and oxa-adamantane (2-oxatricyclo [3.3.1.1 ^{3, 7} ] decane) This includes, but is not limited to. Monocyclic, bicyclic and tricyclic heterocycles can be linked, unsubstituted or substituted to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring.

The term "hydroxyl" or "hydroxy" as used herein means a -OH group.

The term "hydroxyalkyl" as used herein means that at least one -OH group is attached to the parent molecular moiety through an alkylene group as defined herein.

The term "hydroxyfluoroalkyl" as used herein means that at least one -OH group is attached to the parent molecular moiety through a fluoroalkyl group as defined herein.

In some cases, the number of carbon atoms in a hydrocarbyl substituent (eg, alkyl or cycloalkyl) is indicated by the prefix “C _x -C _y- ”, where x is the minimum number of carbon atoms in the substituent and y is It is the maximum number. Thus, for example, “C ₁ -C ₃ -alkyl” refers to an alkyl substituent containing 1 to 3 carbon atoms.

The term "sulfonamide" as used herein means -S (O) ₂ NR- or -NRS (O)-, where R is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, al It can be a kenyl or heteroalkyl.

The term "substituent" refers to a "substituted" group at any atom on an aryl, heteroaryl, phenyl or pyridinyl group. Any atom can be substituted.

The term "substituted" refers to groups that may be further substituted with one or more non-hydrogen substituents. Substituents include halogen, = O (oxo), = S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, Heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, Benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, Carbamate and acyl. For example, when a group is described as “optionally substituted” (eg, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, heterocycle or other group such as R group), halogen , = O (oxo), = S (thioxo), cyano, nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cyclo Alkyl, cycloalkenyl, aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy, benzyloxy, amino , Alkylamino, acylamino, aminoalkyl, arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl, aminosulfonyl, sulfinyl, -COOH, ketone, amide, carbamate and acyl Independent from Can have 0, 1, 2, 3, 4 or 5 substituents.

"는 단일 결합(

) 또는 이중 결합(

)을 지칭한다.Terms "

"Is a single bond (

) Or double bond (

).

For the compounds described herein, groups and substituents thereof can be selected according to the atoms and the permissible valences of the substituents, such that selection and substitution spontaneously alters modifications such as, for example, by rearrangement, cyclization, removal, etc. Resulting in stable compounds that do not suffer.

The term “mAChR M ₄ receptor antagonist” as used herein, is any exogenously administered compound that antagonizes mAChR M ₄ directly or indirectly, eg, in an animal, particularly a mammal (eg, a human). Or a substance.

For the enumeration of numerical ranges herein, each intermediate number with the same precision in between is explicitly considered. For example, for the range of 6 to 9, numbers 7 and 8 are considered in addition to 6 and 9, for the range of 6.0 to 7.0, numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitly considered.

2. Compound

The compounds of the present invention are R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , A, Q and m and any combination of these variables or subvariables thereof (eg, Y ¹ , G, etc.) It has formula I as defined herein.

In one aspect, the compound of Formula I:

[Formula I]

Or a pharmaceutically acceptable salt thereof; here

A is a 5 or 6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S;

Q is selected from NR ^a , O and CR ^b R ^c ;

R ¹ is selected from hydrogen, halo, -OR ^d , C ₁ -C ₄ alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl and optionally substituted heteroaryl;

R ² and R ³ are independently selected from hydrogen, C ₁ -C ₄ alkyl and halo, or R ² and R ³ are taken together to form an oxo group;

Each R ⁴ is independently selected from halo, C ₁ -C ₄ alkyl and -OR ^e ;

R ⁵ and R ⁶ are independently selected from hydrogen, C ₁ -C ₈ alkyl and-(CR ^f R ^g ) _n -Y ¹ ;

Each Y ¹ is independently selected from an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycle, an optionally substituted aryl and an optionally substituted heteroaryl;

Each R ^a , R ^b , R ^c , R ^d , R ^e , R ^f and R ^g is independently selected from hydrogen, C ₁ -C ₄ alkyl and aryl;

m is 0, 1 or 2;

n is 0, 1 or 2.

In some embodiments, Q is NR ^a . In some embodiments, R ^a is hydrogen or C ₁ -C ₄ alkyl. In some embodiments, R ^a is hydrogen.

In some embodiments, R ¹ is hydrogen, halo (eg, chloro), -CH = CH-C ₁ -C ₄ alkyl, -CH = CH-G, C ₅ -C ₈ cycloalkenyl, from 4 to 4 Selected from 8-membered monocyclic heterocyclyl, 6-12 membered aryl, and 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S Become; Wherein cycloalkenyl, heterocyclyl, aryl and heteroaryl are unsubstituted, C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ Substituted with 1, 2 or 3 substituents independently selected from haloalkoxy and -NHCOR '; G is ₁ , 2 or independently selected from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' 6 to 12 membered aryl optionally substituted with 3 substituents; R ', in each case, is independently C ₁ -C ₄ alkyl. In a further embodiment, R ¹ is halo, -CH = CH-C ₁ -C ₄ alkyl, -CH = CH-G, C ₅ -C ₈ cycloalkenyl, 4-8 membered monocyclic heterocyclyl , 6 to 12 membered aryl, and 5 to 6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; Wherein cycloalkenyl, heterocyclyl, aryl and heteroaryl are unsubstituted, C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ Substituted with 1, 2 or 3 substituents independently selected from haloalkoxy and -NHCOR '; G is ₁ , 2 or independently selected from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' 6 to 12 membered aryl optionally substituted with 3 substituents; R ', in each case, is independently C ₁ -C ₄ alkyl. In a further embodiment, R ¹ is hydrogen, phenyl, naphthyl (eg 2-naphthyl), benzodioxolyl (eg benzodioxol-5-yl), pyrazolyl (eg, Pyrazole-3-yl, pyrazole-4-yl), isooxazolyl (eg isooxazol-4-yl), thienyl (eg 2-thienyl), pyridinyl (eg For example, pyridin-3-yl), quinolinyl (eg, quinoline-6-yl), isoquinolinyl (eg, isoquinolin-7-yl), piperidinyl (eg, blood Peridin-1-yl), pyrrolidinyl (eg, pyrrolidin-1-yl), morpholinyl (eg, morpholine-4-yl), cyclopentenyl (eg, cyclo Penten-1-yl) or -CH = CH-G, where phenyl, naphthyl, benzodioxolyl, pyrazolyl, isooxazolyl, thienyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl , Pyrrolidinyl, morpholinyl and cyclopentenyl are unsubstituted, methyl, fluoro, chloro, trifluoromethyl, Substituted with 1, 2 or 3 substituents independently selected from trifluoromethoxy, methoxy and cyano; G is ₁ , 2 or independently selected from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' Phenyl optionally substituted with 3 substituents, where R 'is C ₁ -C ₄ alkyl. In a further embodiment, R ¹ is phenyl, pyrazolyl, piperidinyl, pyrrolidinyl, morpholinyl, cyclopentenyl or -CH = CH-G, where phenyl, pyrazolyl, piperidinyl and pyrrolidin Dynyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy and cyano; G is ₁ , 2 or independently selected from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' Phenyl optionally substituted with 3 substituents, where R 'is C ₁ -C ₄ alkyl. In a still further embodiment, G is phenyl substituted with C ₁ -C ₄ alkyl.

In some embodiments, R ¹ is halo; Aryl; And 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; Where aryl and heteroaryl are unsubstituted or independent from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' Substituted with 1, 2 or 3 substituents, wherein R 'is C ₁ -C ₄ alkyl. In some embodiments, R ¹ is halo (eg, chloro). In some embodiments, R ¹ is selected from phenyl, pyrazolyl, thiophene, quinoyl, benzodioxolyl, naphthyl, pyridyl and isooxazolyl, each of which is unsubstituted or C ₁ -C ₄ alkyl , Halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ', independently substituted with 1, 2 or 3 substituents, wherein R 'is C ₁ -C ₄ alkyl. In some embodiments, R ¹ is phenyl or pyrazolyl, wherein phenyl and pyrazolyl are unsubstituted or independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy and cyano It is substituted with 1, 2 or 3 substituents. In some embodiments, R ¹ is unsubstituted, C ₁ -C ₄ alkyl (eg, methyl), halo (eg, fluoro or chloro), cyano, C ₁ -C ₄ haloalkyl (eg For example, ₁ independently selected from trifluoromethyl), C ₁ -C ₄ alkoxy (eg methoxy), C ₁ -C ₄ haloalkoxy (eg trifluoromethoxy) and -NHCOR '. Phenyl substituted with one or two substituents, where R 'is C ₁ -C ₄ alkyl (eg, -NHCOCH ₃ ). In some embodiments, R ¹ is with one or two substituents independently selected from C ₁ -C ₄ alkyl (eg, methyl) and C ₁ -C ₄ haloalkyl (eg, trifluoromethyl). It is substituted pyrazolyl.

In some embodiments, R ¹ is

이다.

to be.

In some embodiments, R ² is hydrogen and R ³ is hydrogen. In some embodiments, R ² and R ³ are taken together to form an oxo group.

In some embodiments, m is 0.

In some embodiments, R ⁵ is hydrogen.

In some embodiments, R ⁶ is selected from C ₁ -C ₈ alkyl and-(CR ^f R ^g ) _n -Y ¹ .

In some embodiments, R ⁶ is selected from C ₁ -C ₈ alkyl and-(CR ^f R ^g ) _n -Y ¹ ; R ^f is hydrogen; R ^g is selected from hydrogen, C ₁ -C ₄ alkyl and phenyl; n is 0 or 1; Y ¹ is C ₃ -C ₁₀ -cycloalkyl; C ₅ -C ₁₀ -cycloalkenyl; Phenyl; 5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; And 5 to 8 membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S; Wherein cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl are unsubstituted or substituted with one or two substituents independently selected from C ₁ -C ₄ alkyl, halo and C ₁ -C ₄ haloalkyl. . In some embodiments, R ⁶ is C ₁ -C ₈ alkyl (eg, methyl, ethyl, isopropyl, sec -butyl, neopentyl, sec -pentyl, 4,4-dimethylpentan-2-yl). In some embodiments, R ⁶ is-(CR ^f R ^g ) _n -Y ¹ , n is 0 or 1, R ^f is hydrogen, R ^g is hydrogen, and Y ¹ is C ₃ -C ₁₀ -cyclo Alkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl), C ₅ -C ₁₀ -cycloalkenyl (eg, bicyclo [2.2.1] hep-5-ene- 2-yl) 5- to 8-membered heterocyclyl having 1 or 2 heteroatoms independently selected from phenyl, N, O and S (eg tetrahydrofuranyl, tetrahydropyranyl, 7- Oxabicyclo [2.2.1] heptanyl), and from 5 to 6 membered heteroaryls (eg, pyridyl) having 1, 2 or 3 heteroatoms independently selected from N, O and S Selected, wherein cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl are unsubstituted, C ₁ -C ₄ alkyl, halo and C ₁ -C ₄ haloalkylobu Is independently substituted with one or two substituents.

In some embodiments, A is a 5-membered heteroaryl having 1 nitrogen atom and optionally 1 to 2 additional heteroatoms independently selected from N, O and S, a 6-membered heterocycle having 1 to 2 nitrogen atoms Aryl, phthalazinyl, imidazo [1,2-b] pyridazinyl or [1,2,4] triazolo [4,3-b] pyridazinyl, where A is halo, C ₁ -C ₄ Optionally substituted with 1 to 4 substituents independently selected from alkyl and C ₁ -C ₄ haloalkyl. In a further embodiment, A is thiazole-2,5-diyl, pyridazine-3,6-diyl, pyrazine-2,5-diyl, pyridine-2,5-diyl, phthalazine-1,4- Diyl, imidazo [1,2-b] pyridazine-6-yl or [1,2,4] triazolo [4,3-b] pyridazine-6-yl, where A is halo, C _1- It is optionally substituted with 1 to 4 substituents independently selected from C ₄ alkyl and C ₁ -C ₄ haloalkyl.

In some embodiments, A is

로부터 선택된다:

Is selected from:

Where T is selected from O, S and NH; U, V, W, X, Y and Z are independently selected from N and CH, wherein 1 to 3 of W, X, Y and Z are N.

In some embodiments, A is

로부터 선택된다.

Is selected from.

In some embodiments, A is

이다. 일부 구현예에서, R¹-A는

이다(즉, 화학식 I의 R¹은 수소임).

to be. In some embodiments, R ¹ -A is

(Ie, R ¹ in Formula I is hydrogen).

In some embodiments, the compound of Formula I is a compound of Formula Ia:

[Formula Ia]

Here, W, X, Y and Z are independently selected from N and CH, and 1 to 3 of W, X, Y and Z are N.

In some embodiments, one or two of W, X, Y and Z is N. In some embodiments, W and X are N and Y and Z are CH. In some embodiments, W, Y and Z are CH and X is N. In some embodiments, X and Y are N and W and Z are CH.

In some embodiments, the compound of Formula I is a compound of Formula Ib:

[Formula Ib]

.

.

Representative compounds of Formula I include, but are not limited to:

6- (2-Chloro-5-fluorophenyl) -N -[[6-[[3- (trifluoromethyl) -2-pyridyl] methyl] -6-azaspiro [2.5] octane-2- 1] methyl] pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (4-fluorophenyl) pyridazine-3-amine;

N -((6-(((1 R , 2 R , 4 S ) -7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl ) Methyl) -6- (1,3-dimethyl- 1H -pyrazol-4-yl) pyridazine-3-amine;

N- [6- (2,4-dimethylpyrazol-3-yl) pyridazin-3-yl] -6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octane-2- Carboxamide;

N- (6- (1,4-dimethyl-1 H -pyrazol-5-yl) pyridazin-3-yl) -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octane- 1-carboxamide;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (1,3-dimethylpyrazol-4-yl) pyridin-2- Amine;

6- (5-bicyclo [2.2.1] hept-2-enyl-methyl) - N - [6- (2,4- dimethyl-pyrazol-3-yl) pyridazin-3-yl] -6-aza-spiro [2.5] octane-2-carboxamide;

N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazole -4-yl) pyridazine-3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;

N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-chloro-5-fluoro Ro-phenyl) pyridazine-3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N -[[6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3- Amine;

6- (2-chloro-5-fluoro-phenyl) -N -[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine; Compound 14

6- (2-Chloro-5-fluoro-phenyl) -N -[[6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine; Compound 15

N -[[6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-chloro-5-fluoro-phenyl) pyridazine-3- Amine;

6- (2-Chloro-5-fluoro-phenyl) -N -[[6- (2,2-diphenylethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3 -Amine;

6- (5-bicyclo [2.2.1] hept-2-enyl-methyl) - N - -6- azaspiro [6- (2-chloro-5-fluorophenyl) pyridazin-3-yl] - 2.5] octane-2-carboxamide;

N- [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] -6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octane-2-car Copy mid;

6-chloro- N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (1,3-dimethylpyrazole -4-yl) pyrazin-2-amine;

5- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyrazine- 2-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (1,3-dimethylpyrazol-4-yl) pyrazin-2- Amine;

6- (2-Chloro-4-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3- Amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (4-methyl-3-pyridyl) pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-fluorophenyl) pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (3-fluorophenyl) pyridazine-3-amine;

6- (2,4-difluorophenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (5-fluoro-2-methyl-phenyl) pyridazine-3- Amine;

6- (2,5-difluorophenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (5-fluoro-2-methoxy-phenyl) pyridazine-3 -Amine;

6- (3,4-difluorophenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

6- (3,5-difluorophenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-phenyl-pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2,4-dimethylpyrazol-3-yl) pyridazine-3 -Amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3,5-trimethylpyrazol-4-yl) pyridazine -3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (3,5-dimethylisooxazol-4-yl) pyridazine-3 -Amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-methylpyrazol-3-yl) pyridazine-3-amine ;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- [2-methyl-5- (trifluoromethyl) pyrazole-3 -Yl] pyridazine-3-amine;

N- [4- [6-[[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] amino] pyridazin-3-yl] phenyl] acetamide ;

6- (2-Chloro-3-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3- Amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (3-methyl-2-thienyl) pyridazine-3-amine;

2- [6-[[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] amino] pyridazin-3-yl] -4-fluoro-benzo Nitrile;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (7-isoquinolyl) pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (6-quinolyl) pyridazine-3-amine;

6- (1,3-benzodioxol-5-yl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3 -Amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-naphthyl) pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- [2- (trifluoromethoxy) phenyl] pyridazine-3-amine ;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- [4- (trifluoromethyl) -3-pyridyl] pyridazine -3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3 -Amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2-methylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine ;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2-methylpentyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine ;

6- (1,3-dimethylpyrazol-4-yl) -N -[(6-ethyl-6-azaspiro [2.5] octan-2-yl) methyl] pyridazine-3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[(6-propyl-6-azaspiro [2.5] octan-2-yl) methyl] pyridazine-3-amine;

N -[[6- (cyclopropylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3-amine;

N -[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3-amine;

N -[[6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3 -Amine;

N -[(6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2,2-diphenylethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6-[(3-methyl-2-pyridyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl ] Pyridazine-3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6-[[3- (trifluoromethyl) -2-pyridyl] methyl] -6-azaspiro [2.5] octane- 2-yl] methyl] pyridazine-3-amine;

(R) -6- (2-chloro-5-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyri Chopped-3-amine;

(R) -6- (2-chloro-5-fluoro-phenyl) -N -[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3 -Amine;

(S) -6- (2-chloro-5-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyri Chopped-3-amine;

(S) -6- (2-chloro-5-fluoro-phenyl) -N -[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3 -Amine;

N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (2-chloro-5-fluoro Ro-phenyl) pyridin-2-amine;

5- (2-chloro-5-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridin-2-amine ;

N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (1,3-dimethylpyrazole -4-yl) pyridin-2-amine;

6- (2,4-dimethylpyrazol-3-yl) -N -[[6- (2-tetrahydrofuran-2-ylethyl) -6-azaspiro [2.5] octan-2-yl] methyl] Pyridazine-3-amine;

N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5-phenyl-thiazole-2-amine ;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5-phenyl-thiazol-2-amine;

5-phenyl- N -[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] thiazol-2-amine;

6- (2,4-Dimethylpyrazol-3-yl) -N -[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;

6- (3,3-difluoropyrrolidin-1-yl) -N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyri Chopped-3-amine;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2,4-dimethylpyrazol-3-yl) -N-methyl -Pyridazine-3-amine;

2-[[6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] oxymethyl] -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octane;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1-piperidyl) pyridazine-3-amine;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-morpholino-pyridazine-3-amine;

6- (4,4-difluoro-1-piperidyl) -N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-pyrrolidin-1-yl-pyridazine-3-amine;

N-[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-morpholino-pyridazine-3 -Amine;

N-[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-morpholino-pyridazine-3-amine;

N-[[6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-morpholino-pyridazine-3-amine;

6-morpholino-N-[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

6- (5-Bicyclo [2.2.1] hept-2-enylmethyl) -2-[[6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] oxymethyl] -6 -Azaspiro [2.5] octane;

2-[[6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] oxymethyl] -6- (cyclohexylmethyl) -6-azaspiro [2.5] octane;

N-[(6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl] -4- (1,3-dimethylpyrazol-4-yl) phthalazine-1-amine;

N-[[6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -4- (1,3-dimethylpyrazol-4-yl) phthalazine- 1-amine;

6- (cyclopenten-1-yl) -N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

6-[(E) -3,3-dimethylbut-1-enyl] -N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyri Chopped-3-amine;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-[(E) -2- (p-tolyl) vinyl] pyridazine- 3-amine;

4- (1,3-dimethylpyrazol-4-yl) -N-[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] phthala Jin-1-amine;

N-[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -4- (1,3-dimethylpyrazol-4-yl) phthalazine-1-amine ;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -4- (1,3-dimethylpyrazol-4-yl) phthalazine- 1-amine;

N-[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -4- (1,3-dimethylpyrazole -4-yl) phthalazine-1-amine;

6- (2-Chloro-5-fluoro-phenyl) -N-[[6-[(3-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N-[[6-[(4-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N-[[6-[(4-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N-[[6-[(2-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;

N-[(6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl] -6- (2-chloro-5-fluoro-phenyl) pyridazine-3-amine;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] imidazo [1,2-b] pyridazine-6-amine;

N-[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl]-[1,2,4] triazolo [ 4,3-b] pyridazine-6-amine;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl]-[1,2,4] triazolo [4,3-b] pyridazine- 6-amine;

N-[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl]-[1,2,4] triazolo [4,3-b] pyridazine-6-amine ;

(R) -6- (2-chloro-5-fluoro-phenyl) -N-[[6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl ] Pyridazine-3-amine;

(R) -6- (2-chloro-5-fluoro-phenyl) -N-[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl ] Pyridazine-3-amine;

N-(((1R) -6- (bicyclo [2.2.1] hept-5-en-2-ylmethyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (2 -Chloro-5-fluorophenyl) pyridazine-3-amine;

(R) -6- (2-chloro-5-fluorophenyl) -N-((6- (cycloheptylmethyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazine-3- Amine;

N-(((1R) -6-((7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- ( 2-chloro-5-fluorophenyl) pyridazine-3-amine;

N- [4- [6-[[(2R) -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] Acetamide;

N-[[(2R) -6-benzyl-6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-chloro-5-fluoro-phenyl) pyridazine-3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N-[[(2R) -6- (2-pyridylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N-[[(2R) -6-[(3-methyl-2-pyridyl) methyl] -6-azaspiro [2.5] octane-2- 1] methyl] pyridazine-3-amine;

N-[[(2R) -6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-chloro-5-fluoro-phenyl) pyri Chopped-3-amine;

N- [4- [6-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methylamino] -4,5-dimethyl-pyridazin-3-yl ] Phenyl] acetamide;

N-[4- [6-[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] -4,5-dimethyl-pyridazin-3-yl] phenyl] Acetamide;

N- [4- [6-[[(2R) -6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] acetamide;

N- [4- [6-[[(2R) -6- (cycloheptylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] acetamide;

N- [4- [6-[[(2R) -6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] Acetamide;

N- [4- [6-[[(2R) -6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] Phenyl] acetamide;

N- [4- [6-[[(2R) -6-[(3-methyl-2-pyridyl) methyl] -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazine-3 -Yl] phenyl] acetamide;

N- [4- [6-[[(2R) -6-[(4-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] Phenyl] acetamide;

N- [4- [6-[[(2S) -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] Acetamide;

N- [4- [6-[[(2S) -6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] acetamide;

N- [4- [6-[[(2S) -6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] Phenyl] acetamide;

Or a pharmaceutically acceptable salt thereof.

The experimental section also refers to the compounds described below by the names generated from the structures using ChemDraw® software.

Compounds can exist as stereoisomers with asymmetric or chiral centers present. Stereoisomers are " R " or " S " depending on the placement of the substituents around the chiral carbon atom. The terms “ R ” and “ S ” as used herein refer to Pure Appl. Chem., 1976, 45: 13-30] as defined in section E, IUPAC 1974 recommendations for basic stereochemistry. This specification contemplates various stereoisomers and mixtures thereof, and these are clearly included within the scope of the present invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by decomposition methods well known to those skilled in the art following the preparation of racemic mixtures. This method of degradation is described in chiral adjuvants described in (1) Furniss, Hannaford, Smith, and Tatchell, "Vogel's Textbook of Practical Organic Chemistry," 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England. Attachment of enantiomeric mixtures, recrystallization or chromatographic separation of the resulting diastereomeric mixtures, and selective glass of optically pure products from adjuvants, or (2) direct separation of optical enantiomeric mixtures on chiral chromatography columns , Or (3) fractional recrystallization.

It should be understood that the compounds may have geometric isomers as well as tautomeric forms, and these also constitute embodiments of the present specification.

This specification also includes isotope-labeled compounds identical to those listed in Formula I, except that one or more atoms are replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number generally found in nature. do. Examples of isotopes suitable for inclusion in the compounds of the invention are ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl, respectively. Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, but are not limited thereto. Heavy hydrogen, i.e., can provide more even more greater metabolic stability, for example, a certain therapeutic advantages due to an increased in vivo half-life or reduced need doses substituted with heavier isotopes such as ² H, therefore, some In situations it may be desirable. The compounds may contain positron emitting isotopes for medical imaging and positron emission tomography (PET) studies to determine the distribution of receptors. Suitable proton-releasing isotopes that can be included in the compounds of formula I are ¹¹ C, ¹³ N, ¹⁵ O and ¹⁸ F. Isotopically labeled compounds of Formula (I) are generally subjected to a process similar to that described in the accompanying Examples by conventional techniques known to those skilled in the art or by using appropriate isotope-labeled reagents instead of non-isotopically labeled reagents. Can be produced by.

a. Pharmaceutically acceptable salts

The disclosed compounds may exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is a water-soluble or oil-soluble or dispersible, suitable for the treatment of disorders without excessive toxicity, irritation and allergic reactions, corresponds to a reasonable benefit / risk ratio and is effective for the intended use. Refers to a salt or zwitterion. Salts can be prepared separately during the final isolation and purification of the compound, or by reacting the amino group of the compound with a suitable acid. For example, the compound can be dissolved in a suitable solvent, such as, but not limited to, methanol and water, and treated with at least one equivalent of acid, such as hydrochloric acid. The resulting salt precipitates and can be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, Heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -Phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydro Chloric, hydrobromic, sulfulic, and phosphoric. The amino groups of the compounds can also be quaternized with alkyl chlorides, bromide and iodide, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl, and the like.

The base addition salt is a metal cation such as lithium, sodium, potassium, calcium, magnesium or aluminum, or a compound initiated by reaction of a carboxyl group with a suitable base such as a hydroxide, carbonate or bicarbonate of an organic primary, secondary or tertiary amine. Can be prepared during final isolation and purification. Methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N , N -dimethylaniline, N -methylpiperidine, N-methylmorpholine, dicyclohexylamine , Procaine, dibenzylamine, N , N -dibenzylphenethylamine, 1-ephenamine and N , N' -dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, etc. Quaternary amine salts such as those derived from can be prepared.

b. General synthesis

The compounds of formula I can be prepared by synthetic processes or by metabolic processes. Preparation of compounds by metabolic processes includes those that occur in the body (in vivo) of humans or animals or those that occur in vitro.

The abbreviations used in the description of the schemes below are as follows:

AcOH Acetic acid

BrettPhos-Pd-G3 Methanesulfonato (2-dicyclohexylphosphino-3,6-dimethoxy-2 ', 4', 6'-tri-i-propyl-1,1'-biphenyl) (2'-amino-1 , 1'-biphenyl-2-yl) palladium (II) (CAS number 1470372-59-8)

DCE 1,2-dichloroethane

DCM Dichloromethane

DIPEA N, N -diisopropylethylamine

DMF N , N -dimethylformamide

HATU 1- [bis (dimethylamino) methylene] -1 H -1,2,3-triazolo [4,5- b ] pyridinium 3-oxide hexafluorophosphate

LAH Lithium aluminum hydride

NaBH (OAc) ₃ sodium triacetoxyborohydride

NMP N -methyl-2-pyrrolidone

PyClU 1- (chloro-1-pyrrolidinylmethylene) pyrrolidinium hexafluorophosphate

RuPhos-Pd-G3 Methanesulfonato (2-dicyclohexylphosphino-2 ', 6'-di-i-propoxy-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2- Sun) Palladium (II) (CAS number 1445085-77-7)

SFC Supercritical fluid chromatography

THF Tetrahydrofuran

Compounds of formula (I) can be synthesized as shown in the scheme below.

General scheme A

As shown in Scheme A, Compound A can react with Compound B to yield Compound C, which in the presence of a suitable catalyst is coupled with a suitable boronic acid or ester to yield Compound D. Boc deprotection results in compound E. This process involves the compound of formula I (e.g., where R ² and R ³ are hydrogen, m is 0, where W is CH, X is N, Z is CH, or W is CH, X Is CH and Z is N) (ie, a compound of formula Ib) can be used to prepare a precursor.

General Reaction Scheme B

As shown in Scheme B in general, compound E can react with suitable aldehydes and sodium triacetoxyborohydride to yield compound F. This process involves the compound of formula I (e.g., R ² , R ³ and R ⁵ are hydrogen, m is 0, where W is CH, X is N, Z is CH, or W is CH , X is CH, and Z is N) (i.e., a compound of formula Ib).

General Reaction Scheme C

Suitable heteroaryl compounds G functionalized with halo groups (e.g., F or Cl), as shown in Scheme C, wherein A is a 5 or 6 membered heteroaryl as defined herein, and R ¹ (As defined herein) can be coupled to Compound A, resulting in Compound H, which can be deprotected and coupled as described herein or according to other known methods. This process is for compounds of formula I, wherein R ² and R ³ are hydrogen, m is 0, and A is as defined herein (e.g., A is pyridyl or thiazolyl). It can be used to prepare precursors.

General Reaction Scheme D

As shown in Scheme D, compound C '(corresponding to Compound C, where W is CH, X is CH, and Z is N) is deprotected followed by 3,3-dimethylbutyraldehyde and Can react with sodium triacetoxyborohydride to yield compound I, which can be coupled with a suitable boronic acid or ester in the presence of a suitable catalyst to yield compound J. This process can be used to prepare certain compounds of formula I, e.g., compounds of formula Ib, wherein R ² and R ³ are hydrogen, R ⁵ is hydrogen, and R ⁶ is neopentyl.

Scheme E

As shown in Scheme E, certain compounds are prepared by combining Compound K with rac- (1 R , 2 S , 4 S ) -7-oxabicyclo [2.2.1] heptan-2-carboxylic acid in the presence of HATU and DIPEA. It can be prepared from compound K (prepared according to general scheme A) by reacting to produce compound L, which can be reduced using lithium aluminum hydride to yield compound M.

Scheme F

As shown in Scheme F, another specific compound can be prepared from Compound K. Reaction with 2- (2-bromoethyl) oxolane produces compound N.

General Reaction Scheme G

As shown in the general scheme G, compounds such as compound C 'can be subjected to chiral separation, if desired, to separate enantiomers.

General Reaction Scheme H

As shown in General Reaction Scheme H, a given compound of Formula I reacts Compound Q with 3-amino-6-chloropyridazine and PyClU to form Compound R, which in the presence of a suitable catalyst is a suitable boronic acid or ester. It can be coupled with a compound S to produce. Deprotection and reaction with suitable aldehydes and sodium triacetoxyborohydride results in compound T. This procedure can be used to prepare certain compounds of formula I, such as compounds of formula Ib, wherein R ² and R ³ are taken together to form an oxo group and R ⁵ is hydrogen.

General Reaction Scheme I

As shown in general scheme I, compounds of formula I, wherein R ¹ is an amine-containing group attached via nitrogen, can be prepared by reacting and heating a suitable amine with chloropyridazine in the presence of a base in an organic solvent. . Microwave irradiation can facilitate the reaction. In Scheme I, L is an O, N, S or methylene group, and R ^1a is an optional substituent on R ¹ as defined herein. Although illustrated in Scheme I for cyclic amine R ¹ groups, the methodology can also be applied to bicyclic amine -N (R ^d ) ₂ .

General Reaction Scheme J

General Scheme J illustrates a similar manufacturing sequence to Schemes A and B for preparing compounds of Formula I, where Q is NR ^a and R ^a is an alkyl group. The Suzuki, Boc deprotection and reductive amination steps are generally similar to those described elsewhere herein.

General Reaction Scheme K

General Scheme K illustrates the sequence for preparing compounds of Formula I, where Q is O. The Suzuki, Boc deprotection and reductive amination steps are generally similar to those described elsewhere herein.

Compounds and intermediates can be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds include, for example, Vogel's Textbook of Practical Organic Chemistry, "5th edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub.Longman Scientific & Technical, Essex CM20 2JE, England] by chromatography on a solid support such as silica gel, alumina or silica derivatized with an alkylsilane group, by recrystallization at high or low temperature with selective pretreatment with activated carbon. , Thin layer chromatography, distillation at various pressures, sublimation and grinding under vacuum, but are not limited thereto.

The disclosed compounds can have at least one basic nitrogen, whereby the compounds can be treated with an acid to form the desired salt. For example, the compound can react with an acid above room temperature to provide the desired salt, which accumulates and collects by filtration after cooling. Examples of suitable acids for the reaction are not only tartaric acid, lactic acid and succinic acid, but also mandelic acid, atrolactic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carbonic acid, fumaric acid, maleic acid Acids, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid and the like. Does not.

The reaction conditions and reaction time for each individual step can vary depending on the particular reactants used and the substituents present on the reactants used. Specific procedures are provided in the Examples section. The reaction can be developed in a conventional manner, e.g., by removing the solvent from the residue, and to methodologies generally known in the art, such as, but not limited to, crystallization, distillation, extraction, grinding and chromatography. It can thus be further purified. Unless otherwise stated, starting materials and reagents are commercially available or can be prepared by those skilled in the art from commercially available materials using methods described in chemical literature. If not commercially available, starting materials will be prepared by procedures selected from standard organic chemistry techniques, techniques analogous to the synthesis of known and structurally similar compounds, or techniques similar to those described in the Schemes or Synthetic Examples section above. You can.

Routine experiments, including the appropriate manipulation of the reaction conditions, the order of reagents and synthetic routes, protection of any chemical functionality incompatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method, are routine It is included within the scope. Suitable protecting groups and methods of protecting and deprotecting different substituents using these suitable protecting groups are well known to those skilled in the art; Examples of this can be found in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4 ^th ed.), John Wiley & Sons, NY (2006), the entirety of which is incorporated herein by reference. do. Synthesis of the compounds of the present invention can be accomplished by methods analogous to those described in the synthetic schemes and specific examples described hereinabove.

If the optically active form of the disclosed compounds is desired, it can be performed by performing one of the procedures described herein using an optically active starting material (e.g., prepared by asymmetric induction of a suitable reaction step), or a standard procedure (e.g. For example, it can be obtained by decomposition of a mixture of stereoisomers of compounds or intermediates using chromatographic separation, recrystallization or enzymatic digestion.

Similarly, if pure geometric isomers of a compound are desired, either by performing one of the above procedures using pure geometric isomers as starting material, or for decomposition of a mixture of geometric isomers of a compound or intermediate using standard procedures such as chromatographic separation. Can be obtained by

It is understood that the described synthetic schemes and specific examples are exemplary, and that the scope of the invention is defined in the appended claims and should not be read as limiting the scope of the invention. All alternatives, modifications and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

c. Muscarinic  Acetylcholine receptor M ₄  activation

M ₄ is the most highly expressed mAChR subtype in striatum and its expression is similar in rodents and primates. Due to the lack of selective M ₄ antagonist, a mechanistic understanding of the role of M ₄ is a biochemical and genetic studies, and highly selective M ₄ positive allosteric modulators: is led by the use of a (positive allosteric modulator PAM). The highly selective M ₄ PAM induces a strong decrease in the behavioral response to psychomotor stimulants that act by increasing striatal DA levels. Moreover, gene deletion of M ₄ increases exploratory locomotor activity, enhances the locomotor response to amphetamines and other stimulants, eliminates the effect of M ₄ PAM on locomotor activity, and this effect is It is also observed with selective deletion of M ₄ from striatal visibility projection neurons expressing the D1 subtype of the DA receptor (D1-SPN). In vivo microdialysis studies have revealed that administration of M ₄ PAM reduces amphetamine-induced DA release in ventral and ventral striatum, and fMRI studies have shown that M ₄ PAM has cerebral blood flow (CBV) in the striatum and other basal ganglia. It indicates that it reverses the amphetamine induced increase in. More recently, fast-scanning cyclic voltammetry (FSCV) and genetic studies have shown that M ₄ PAM releases endocannabinoids, at least in part, from striatal spiny projection neurons (SPNs). And activation of the CB2 cannabinoid receptor at the DA end, thereby acting by inhibition of DA release from the presynaptic DA end in the striatum.

M ₄ is in the subunit (D1-SPN) of the SPN that also expresses the D ₁ subtype of the DA receptor (D ₁ DR), which forms a direct pathway to the inhibitory process to the substantia nigra pars reticulata (SNr). It is highly expressed. Interestingly, D ₁ DR couples D ₁ R to activation of adenylate cyclase, formation of cAMP and activation of protein kinase A (PKA), in D1-SPN, _termed G _αolf . Activates the unique GTP binding protein. This signaling pathway is important for many behavioral actions of DA-mediated activation of motor activity. Interestingly, M ₄ couples to the Gα _{i / o} G protein, which has the potential to inhibit adenylate cyclase and respond directly to the effect on inhibitory D ₁ receptor signaling and motor function. This study raised the possibility that, in addition to the inhibition of DA release, M ₄ PAM could directly inhibit D1R-mediated signaling in D ₁ -SPN by direct inhibition of cAMP formation, which also DA signaling in the basal ganglia. May contribute to the potent inhibitory effect of selective M ₄ activation. Consistent with this, M ₄ PAM inhibits the locomotor stimulating effect of direct acting D ₁ agonists. Moreover, a series of pharmacological, genetic and molecular / cell studies revealed that this response is mediated by inhibition of D ₁ DR signaling in D1-SPN. Thus, the main action of M ₄ PAM on D ₁ DR signaling is at the GABA-like end of D ₁ -SPN at SNr, not at the striatum, where activation of D ₁ DR leads to a strong increase in GABA release. This challenges various views that cholinergic regulation of striatal function is almost exclusively mediated through ACh released from tonically active striatum cholinergic interneurons (ChIs), and from cholinergic projections from the cerebral cortical brain nuclei. The possibility that SNr's cholinergic neurodistribution can also play an important role in modulating motor activity and other functions of the basal ganglia direct pathway. Taken together, these data suggest that, in addition to inhibiting DA release, M ₄ activation also acts on D ₁ -expressing SPN after synapses to inhibit motor function.

The primary mAChR in line with the important role of the sub-types as M _4, a number of reports mAChR antagonist Skopje Paula seeds Loco Motors participates in regulating the movement - enable effective four other mAChR subtypes (M ₁ - _{3, 5} ) but not in M ₄ knockout mice. Moreover, haloperidol induced stiffness, a model of Parkinson's disease behavioral disorder, is reduced in M ₄ knockout mice compared to wild type controls. By evaluating the effect of this compound on the stiffness induced by the DA receptor antagonist haloperidol, evaluation of the antiparkinson's effect of scopolamine indicates potent stiffness completely reversed by scopolamine in WT mice. Reversal by scopolamine is an agent targeting a number of other targets that are evaluated for potential anti-Parkinson's disease effects, including the metabolic stimulatory glutamate (mGlu) receptor mGlu ₄ or mGlu ₅ , A ₂ A adenosine receptor, and NMDA receptor. By virtue of the present inventors, it was very strong and more distinct than observed. Importantly, scopolamine is ineffective in reducing stiffness in M ₄ KO mice, suggesting that the antispasmodic effect of scopolamine requires action on mAChR M ₄ . Along with extensive studies of M ₄ regulation and motor function of the basal nucleus, this study provides convincing evidence that M ₄ is the predominant mAChR subtype involved in the anti-Parkinson's disease effects of non-selective mAChR antagonists, PD, dystonia, It assists in the discovery and development of selective M ₄ antagonists for the treatment of neurodegenerative diseases such as tardive dyskinesia and other movement disorders.

Despite progress in mAChR investigations, there is still a lack of compounds that are powerful, efficient and selective antagonists of M ₄ mAChR. Highly selective M ₄ antagonists represent a novel therapeutic approach for the treatment of neurodegenerative diseases including PD, dystonia, delayed dyskinesia and other motor disorders, and of scopolamine without side effects mediated by pan- mAChR inhibition. Can provide clinical benefit.

In some embodiments, disclosed compounds are antagonists of mAChR M ₄ . Such activity can be demonstrated by methodologies known in the art. For example, the antagonism of the mAChR M ₄ activity of Ca ^{2 +} - sensitive fluorescent dyes (e.g., Fluo-4) agent in which the loading cell, for example, the measurement of calcium flux responses to acetylcholine And co-expression of chimeric or hybrid G proteins. In some embodiments, calcium flux can be measured as an increase in the fluorescence static ratio. In some embodiments, antagonist activity can be analyzed as a concentration dependent increase in the EC ₈₀ acetylcholine reaction (ie, the reaction of mAChR M ₄ at a concentration of acetylcholine that produces 80% of the maximum response).

In some embodiments, the disclosed compounds is compared to the response of the same CHO-K1 cells in the absence of compound mAChR M ₄ present under the compound thereby antagonize the mAChR M ₄ as a decrease in calcium fluorescence at the plasma injection CHO-K1 cells. In some embodiments, the disclosed compounds antagonize the mAChR M ₄ reaction with an IC ₅₀ of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM. In some embodiments, mAChR M ₄ -transfected CHO-K1 cells are transfected with human mAChR M ₄ . In some embodiments, mAChR M ₄ -transfected CHO-K1 cells are transfected with rat mAChR M ₄ . In some embodiments, mAChR M ₄ -transfected CHO-K1 cells are transfected with mAChR M ₄ from a dog or cynomolgus monkey.

The disclosed compounds are mAChR M ₄ in mAChR M ₄ -transfected CHO-K1 cells with IC ₅₀ less than IC ₅₀ for one or more of the mAChR M ₁ , M ₂ , M ₃ or M ₅ -transfected CHO-K1 cells. The reaction can be antagonized. That is, the disclosed compounds may have selectivity for the mAChR M ₄ receptor compared to one or more of the mAChR M ₁ , M ₂ , M ₃ or M ₅ receptors. For example, in some embodiments, the disclosed compounds are about 5 times less, about 10 times less, about 20 times less, about 30 times less, about 50 times less, about 100 times less than about mAChR M ₁ The mAChR M ₄ reaction can be antagonized with an IC _{50 that} is 200 times less, about 300 times less, about 400 times less, or more than about 500 times less. In some embodiments, the disclosed compounds are about 5 times less, about 10 times less, about 20 times less, about 30 times less, about 50 times less, about 100 times less, about 200 times less than for mAChR M ₂ , The mAChR M ₄ reaction can be antagonized with an IC _{50 that} is about 300 times less, about 400 times less, or more than about 500 times less. In some embodiments, the disclosed compounds are about 5 times less, about 10 times less, about 20 times less, about 30 times less, about 50 times less, about 100 times less, about 200 times less than for mAChR M ₃ , The mAChR M ₄ reaction can be antagonized with an IC _{50 that} is about 300 times less, about 400 times less, or more than about 500 times less. In some embodiments, the disclosed compounds are about 5 times less, about 10 times less, about 20 times less, about 30 times less, about 50 times less, about 100 times less, about 200 times less than for mAChR M ₅ , The mAChR M ₄ reaction can be antagonized with an IC _{50 that} is about 300 times less, about 400 times less, or more than about 500 times less. In some embodiments, the disclosed compounds are 5 times less, about 10 times less, about 20 times less, about 30 times less, mAChR M ₁ , M ₂ , M ₃ , or M ₅ than for the M ₂ -M ₅ receptor The mAChR M ₄ response can be antagonized with an IC ₅₀ that is about 50 times less, about 100 times less, about 200 times less, about 300 times less, about 400 times less, or more than about 500 times less than for the receptor.

The disclosed compounds with IC ₅₀ of less than about 10 μM M ₄ - transformed and antagonize the mAChR M ₄ response in implanted CHO-K1 _{cells, mAChR M 1, M 2,} M 3 or M ₅ compared to one or more of the receptors, M ₄ Selectivity to receptors can be indicated. For example, in some embodiments, the compound can have an IC ₅₀ of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM; The compound is also about 5 times less, 10 times less, 20 times less, 30 times less, 50 times less, 100 times less, 200 times less, 300 times less, 400 times less, or about 500 than for mAChR M ₁ The mAChR M ₄ reaction can be antagonized with an IC ₅₀ that is less than doubled. In some embodiments, the compound can have an IC ₅₀ of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM; The compound is also about 5 times less, about 10 times less, about 20 times less, about 30 times less, about 50 times less, about 100 times less, about 200 times less, about 300 times less than for mAChR M ₂ , The mAChR M ₄ reaction can be antagonized with an IC ₅₀ of about 400 times less, or more than about 500 times less. In some embodiments, the compound can have an IC ₅₀ of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM; The compound is also about 5 times less, about 10 times less, about 20 times less, about 30 times less, about 50 times less, about 100 times less, about 200 times less, about 300 times less than for mAChR M ₃ , The mAChR M ₄ reaction can be antagonized with an IC ₅₀ of about 400 times less, or more than about 500 times less. In some embodiments, the compound can have an IC ₅₀ of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM; The compound is also about 5 times less, about 10 times less, about 20 times less, about 30 times less, about 50 times less, about 100 times less, about 200 times less, about 300 times less than for mAChR M ₅ , The mAChR M ₄ reaction can be antagonized with an IC ₅₀ of about 400 times less, or more than about 500 times less. In some embodiments, the compound can have an IC ₅₀ of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 50 nM; The compound is also about 5 times less than about the M ₂ -M ₅ receptor, about 10 times less, about 20 times less, about 30 times less than the mAChR M ₁ , M ₂ , M ₃ or M ₅ receptor. Antagonize mAChR M ₄ response with 50 times less, about 100 times less, about 200 times less, about 300 times less, about 400 times less, M ₂ , M ₃ or M ₅ receptor, or IC ₅₀ less than about 500 times less I can do it.

In vivo efficiency for the disclosed compounds in models predicting antiparkinsonism activity can be measured in a number of preclinical rat models. For example, the disclosed compounds can reverse defects in motor function induced by dopamine receptor antagonists in mice or rats. In addition, these compounds are capable of reversing defects in motor function observed by other manipulations that reduce dopamine signaling, such as selective lesions of dopamine neurons. In addition, it is possible that these compounds have efficiency in animal models of dystonia and can increase the degree of attention, cognitive function and motivation in animal models.

3. Pharmaceutical composition and formulation

The disclosed compounds can be incorporated into pharmaceutical compositions suitable for administration to a subject (eg, a human or non-human patient). The disclosed compounds can also be provided as formulations, such as spray-dried dispersion formulations.

Pharmaceutical compositions and formulations may include a "therapeutically effective amount" or "prophylactically effective amount" of the formulation. “Therapeutically effective amount” refers to an amount effective to achieve the desired therapeutic result, at the required dosage and for a period of time. The therapeutically effective amount of the composition can be determined by one skilled in the art and can vary depending on factors such as the individual's disease state, age, sex and weight, and the ability of the composition to elicit the desired response in the individual. A therapeutically effective amount is also one that has a greater therapeutic benefit than any toxic or deleterious effect of a compound of the invention (eg, a compound of Formula I). “Prophylactically effective amount” refers to an amount effective to achieve the desired preventive result, at the required dosage and for a period of time. Typically, because a prophylactic dose is used in a subject prior to the initial stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

For example, a therapeutically effective amount of a compound of Formula (I) is about 1 mg / kg to about 1000 mg / kg, about 5 mg / kg to about 950 mg / kg, about 10 mg / kg to about 900 mg / kg, about 15 mg / kg to about 850 mg / kg, about 20 mg / kg to about 800 mg / kg, about 25 mg / kg to about 750 mg / kg, about 30 mg / kg to about 700 mg / kg, about 35 mg / Kg to about 650 mg / kg, about 40 mg / kg to about 600 mg / kg, about 45 mg / kg to about 550 mg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg To about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 80 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg.

Pharmaceutical compositions and formulations may include a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein means any type of non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation aid. Some examples of substances that can be used as pharmaceutically acceptable carriers include sugars, such as, but not limited to, lactose, glucose and sucrose; Starch, such as, but not limited to, corn starch and potato starch; Cellulose and its derivatives, such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powder tragacanth; malt; gelatin; talc; Excipients, such as, but not limited to, cocoa butter and suppository waxes; Oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; Such as propylene glycol; Glycol; Esters, such as, but not limited to, ethyl oleate and ethyl laurate; Baby; Buffering agents, such as, but not limited to, magnesium hydroxide and aluminum hydroxide; Alginic acid; Pyrogen-free water; Isotonic saline; Ringer's solution; Ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants, such as, but not limited to, sodium lauryl sulfate and magnesium stearate, and colorants, mold release agents, coatings, sweeteners, as the manufacturer determines , Spices and fragrances, preservatives and antioxidants can also be present in the composition.

Thus, the compounds and physiologically acceptable salts thereof are, for example, solid dosages, eye drops, topical oily formulations, injections, inhalants (via mouth or nose), implants, or oral, buccal, parenteral, Or it can be formulated for administration by rectal administration. Techniques and formulations can generally be found in "Remington's Pharmaceutical Sciences," (Meade Publishing Co., Easton, Pa.). The therapeutic composition should typically be sterile and stable under the conditions of manufacture and storage.

The route of administration of the disclosed compounds and the form of the composition will determine the type of carrier to be used. The composition may be, for example, systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant or parenteral) or topical administration (e.g., skin, lung, nose, ear, eye, liposome delivery system or Ion implantation method).

Carriers for systemic administration typically include at least one of a diluent, lubricant, binder, disintegrant, colorant, flavor, sweetener, antioxidant, preservative, fluidizing agent, solvent, suspending agent, wetting agent, surfactant, combinations thereof, and the like. Is included. All carriers are optional in the composition.

Suitable diluents include sugars such as glucose, lactose, dextrose and sucrose; Diols such as propylene glycol; Calcium carbonate; Sodium carbonate; Sugar alcohols such as glycerin; Mannitol; And sorbitol. The amount of diluent (s) in the systemic or topical composition is typically from about 50% to about 90%.

Suitable lubricants include silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate; And liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and theobroma oil. The amount of lubricant (s) in the systemic or topical composition is typically from about 5% to about 10%.

Suitable binders include polyvinyl pyrrolidone; Magnesium silicate aluminum; Starch such as corn starch and potato starch; gelatin; Tragacanth; And cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, methyl cellulose, microcrystalline cellulose and sodium carboxymethylcellulose. The amount of binder (s) in the systemic composition is typically from about 5% to about 50%.

Suitable disintegrants include agar, alginic acid and its sodium salt, saturating agents, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clay and ion exchange resins. The amount of disintegrant (s) in the systemic or topical composition is typically from about 0.1% to about 10%.

Suitable colorants include colorants such as FD & C dyes. When used, the amount of colorant in the systemic or topical composition is typically from about 0.005% to about 0.1%.

Suitable flavoring agents include menthol, peppermint and fruit flavors. When used, the amount of flavor (s) in the systemic or topical composition is typically from about 0.1% to about 1.0%.

Suitable sweeteners include aspartame and saccharin. The amount of sweetener (s) in the systemic or topical composition is typically from about 0.001% to about 1%.

Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT") and vitamin E. The amount of antioxidant (s) in the systemic or topical composition is typically from about 0.1% to about 5%.

Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative (s) in the systemic or topical composition is typically from about 0.01% to about 5%.

Suitable fluidizing agents include silicon dioxide. The amount of fluidizing agent (s) in the systemic or topical composition is typically from about 1% to about 5%.

Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oil, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent (s) in the systemic or topical composition is typically from about 0% to about 100%.

Suitable suspending agents include AVICEL RC-591 (manufactured by FMC Corporation of Philadelphia, Pennsylvania) and sodium alginate. The amount of suspension (s) in the systemic or topical composition is typically about 1% to about 8%.

Suitable surfactants include lecithin, polysorbate 80 and sodium lauryl sulfate, and TWEENS of Atlas Powder Company of Wilmington, Delaware. Suitable surfactants are described in C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp. 587-592; Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant (s) in the systemic or topical composition is typically from about 0.1% to about 5%.

The amount of component in the systemic composition may vary depending on the type of systemic composition prepared, but in general, the systemic composition is from 0.01% to 50% of the active compound (e.g., a compound of Formula I) and 50% to 99.99% The above carrier is included. Compositions for parenteral administration typically include a carrier comprising 0.1% to 10% of active agent and 90% to 99.9% of diluent and solvent.

Compositions for oral administration may have a variety of dosage forms. For example, solid forms include tablets, capsules, granules and bulk powders. These oral dosage forms include safe and effective amounts, generally at least about 5%, more specifically about 25% to about 50% of the active agent. The oral dosage composition comprises from about 50% to about 95% of the carrier, more specifically from about 50% to about 75%.

Tablets can be compressed, tablet milled, enteric-coated, sugar-coated, film-coated or multi-compressed. Tablets typically include a carrier comprising an active ingredient and a component selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, fluidizing agents, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Specific binders include starch, gelatin and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid and talc. Specific colorants are FD & C dyes that can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavor, or combinations thereof.

Capsules (including implants, sustained release and sustained release formulations) typically include a carrier comprising the active compound (eg, a compound of Formula I) and one or more diluents disclosed above in a capsule comprising gelatin. Granules typically include the disclosed compounds, and preferably a fluidizing agent such as silicon dioxide to improve flow properties. The implant can be of the biodegradable or non-biodegradable type.

The choice of ingredients in the carrier for oral compositions depends on secondary considerations such as taste, cost and storage stability, which is not important for the purposes of the present invention.

Solid compositions can be released by conventional methods, typically with a pH or time-dependent coating, such that the disclosed compounds are released from the gastrointestinal tract near the intended use or at various points and times to prolong the desired action. The coating typically comprises one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Evonik Industries, Essen, Germany), wax and shellac. Includes.

Compositions for oral administration may have a liquid form. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted with non-foamable granules, suspensions reconstituted with non-foamable granules, blowing agents reconstituted with expandable granules, elixirs, tinctures, syrups, and the like. Liquid oral dosage compositions typically include the disclosed compounds and carriers, ie carriers selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Oral liquid compositions preferably include one or more ingredients selected from colorants, flavors and sweeteners.

Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more soluble filler materials such as diluents including sucrose, sorbitol and mannitol; And binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavoring agents, sweetening agents, antioxidants and fluidizing agents.

The disclosed compounds can be administered topically. Topical compositions that can be applied topically to the skin include any solids, solutions, oils, creams, ointments, gels, lotions, shampoos, hair conditioners that leave and rinse, milk, cleansers, moisturizers, sprays, skin patches, etc It may be in the form of. Topical compositions include: disclosed compounds (eg, compounds of Formula I) and carriers. The carrier of the topical composition preferably aids the penetration of the compound into the skin. The carrier may further include one or more optional ingredients.

The amount of carrier used with the disclosed compounds is sufficient to provide a substantial amount of the composition for administration per unit dose of the compound. Techniques and compositions for preparing dosage forms useful in the methods of the present invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

The carrier can include a single component or a combination of two or more components. In topical compositions, the carrier includes a topical carrier. Suitable topical carriers include phosphate buffered saline, isotonic water, deionized water, monofunctional alcohol, symmetrical alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate , Dimethyl isosorbide, castor oil, combinations thereof, and the like. More specifically, carriers for skin application include propylene glycol, dimethyl isosorbide and water, and even more specifically, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohol and symmetrical alcohol.

The carrier of the topical composition may further comprise one or more components selected from emollients, propellants, solvents, wetting agents, thickeners, powders, fragrances, pigments and preservatives, all of which are optional.

Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stear Acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl seba Kate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, peanut oil, castor oil, acetylated lanolin alcohol, petroleum, Mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate , Myristyl myristate, and combinations thereof. Specific emollients for the skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient (s) in the skin-based topical composition is typically from about 5% to about 95%.

Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant (s) in the topical composition is typically from about 0% to about 95%.

Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and Combinations of the above are included. Specific solvents include ethyl alcohol and homotopic alcohol. The amount of solvent (s) in the topical composition is typically from about 0% to about 95%.

Suitable wetting agents include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific wetting agents include glycerin. The amount of wetting agent (s) in the topical composition is typically 0% to 95%.

The amount of thickener (s) in the topical composition is typically from about 0% to about 95%.

Suitable powders include beta-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, clay, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkyl ammonium smectite, trialkyl aryl ammonium smectite, chemically Modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder (s) in the topical composition is typically 0% to 95%.

The amount of fragrance in the topical composition is typically about 0% to about 0.5%, specifically about 0.001% to about 0.1%.

Suitable pH adjusting additives include HCl or NaOH in an amount sufficient to adjust the pH of the topical pharmaceutical composition.

The pharmaceutical composition or formulation may antagonize mAChR M ₄ with an IC ₅₀ of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, or less than about 100 nM. The pharmaceutical composition or formulation may antagonize mAChR M ₄ with an IC ₅₀ of about 10 μM to about 1 nM, about 1 μM to about 1 nM, about 100 nM to about 1 nM, or about 10 nM to about 1 nM. .

a. Spray-dried dispersion formulation

The disclosed compounds can be formulated as a spray-dried dispersion (SDD). SDD is a single phase amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution with molecularly "dissolved" compounds in a solid matrix. SDD is obtained by dissolving the drug and polymer in an organic solvent followed by spray-drying the solution. The use of spray drying for pharmaceutical applications results in an amorphous dispersion with increased solubility Biopharmaceutics Classification System (BCS) Class II (high permeability, low solubility) and Class IV (low permeability, low solubility) drugs. Can cause. The formulation and process conditions are selected such that the solvent evaporates rapidly from the small droplets, resulting in insufficient time for phase separation or crystallization. SDD showed long-term stability and manufacturability. For example, SDDs have a shelf life longer than 2 years. Advantages of SDD include improved oral bioavailability of poorly water-soluble compounds, delivery using conventional solid dosage forms (e.g., tablets and capsules), reproducible, controllable and measurable manufacturing processes and extensive physical properties. Wide applicability to structurally diverse insoluble compounds is included, but not limited to.

Thus, in one embodiment, the present specification can provide a spray-dried dispersion formulation comprising a compound of Formula (I).

4. How to use

The disclosed compounds, pharmaceutical compositions and formulations can be used in methods for the treatment of disorders such as neurological and / or psychiatric disorders associated with muscarinic acetylcholine receptor dysfunction. The disclosed compounds and pharmaceutical compositions can also be used in methods for reducing muscarinic acetylcholine receptor activity in mammals. The method further includes a co-treatment method to improve treatment results. In the methods of use described herein, the additional therapeutic agent (s) can be administered simultaneously or sequentially with the disclosed compounds and compositions.

a. Treatment of disorders

The disclosed compounds, pharmaceutical compositions and formulations can be used in methods for the treatment, prevention, alleviation, control, reduction or reduction of the risk of various disorders or disorders, wherein the patient benefits from antagonism of mAChR M ₄ Will get In some embodiments, the disorder may be neurodegenerative disorder, motor disorder, or brain disorder. The method requires such treatment for a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. And administering to the subject.

Disorders in which the patient is likely to benefit from antagonism of mAChR M ₄ may include neurodegenerative disorders and motor disorders. For example, exemplary disorders include Parkinson's disease, weak toxin Parkinson's syndrome, dystonia, Tourette syndrome, dyskinesia (e.g., delayed dyskinesia or levodopa-induced dyskinesia), schizophrenia, cognitive deficiency associated with schizophrenia, May include excessive daytime sleepiness (eg, narcolepsy), attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea (eg, chorea associated with Huntington's disease), cerebral palsy, and progressive nuclear paralysis have.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Provided is a method of treating motor symptoms in a subject with Parkinson's disease, comprising administering to a subject in need thereof. In some embodiments, the motor symptoms are selected from inflammatory symptoms, tremor, stiffness, gait dysfunction and postural instability. The method may treat motor symptoms in a subject and / or control motor symptoms and / or reduce motor symptoms.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Provided is a method of treating motor symptoms in a subject with dystonia, comprising administering to a subject. The method may treat motor symptoms in a subject and / or control motor symptoms and / or reduce motor symptoms. For example, treatment may reduce muscle contraction or spasm in subjects with dystonia.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Provided is a method of treating motor symptoms in a subject with delayed dyskinesia comprising administering to a subject. The method may treat motor symptoms in a subject and / or control motor symptoms and / or reduce motor symptoms. For example, treatment can reduce involuntary exercise in subjects with delayed dyskinesia.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Provided is a method of preventing or delaying a tardive dyskinesia in a subject at risk of developing a tardive dyskinesia comprising administering to a subject. For example, the subject can be a subject treated with a neuroleptic agent (eg, a typical antipsychotic or atypical antipsychotic), a dopamine antagonist, or an antiemetic agent.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Provided is a method of treating stiffness in a subject suffering from schizophrenia, comprising administering to the subject. For example, a subject with schizophrenia may have stiffness induced by a neuroleptic (eg, a typical antipsychotic or atypical antipsychotic).

In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Provided are methods of treating brain disorders characterized by altered dopamine and cholinergic signaling that benefit from antagonism of mAChR M ₄ comprising administering to the subject. For example, treatment can increase motivation or goal-oriented behavior in patients with a disorder characterized by a reduction in motivation for goal-oriented behavior, such as schizophrenia and other brain disorders.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Provided are methods of increasing arousal and / or reducing excessive daytime sleepiness in a subject in need thereof comprising administering to the subject. In some embodiments, the subject is suffering from narcolepsy.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Provided is a method of increasing attention in a subject (eg, a subject suffering from attention deficit disorder such as ADHD) in a subject in need thereof comprising administering to the subject.

In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. Provided is a method of treating motor symptoms in a subject with weak tonic motor impairment comprising administering to the subject. In some embodiments, the weak tonic movement disorder is selected from weak toxin Parkinson's syndrome, delayed dyskinesia, delayed dystonia, ataxia, interstitial muscle spasm and tremor. The method can treat and / or treat motor symptoms in a subject, control and / or reduce motor symptoms.

The compounds and compositions may further be useful in methods for the prevention, treatment, control, alleviation or reduction of risk of diseases, disorders and conditions mentioned herein. The compounds and compositions can be further useful in methods for the prevention, treatment, control, alleviation or reduction of risk of the diseases, disorders and conditions described above in combination with other agents.

In the treatment of diseases such as those likely to benefit from the antagonism of mAChR M ₄ , an appropriate dosage level can be about 0.01 mg to 500 mg / kg patient body weight daily, which can be administered in single or multiple doses. Dosage levels can be from about 0.1 mg / kg to about 250 mg / kg daily, or from about 0.5 mg / kg to about 100 mg / kg daily. Suitable dosage levels can be from about 0.01 mg / kg to 250 mg / kg daily, from about 0.05 mg / kg to 100 mg / kg daily, or from about 0.1 mg / kg to 50 mg / kg daily. Dosages within this range can be from 0.05 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 5 mg / kg, or 5 mg / kg to 50 mg / kg daily. For oral administration, the composition may be from 1.0 milligram to 1000 milligrams of active ingredient, particularly 1.0, 5.0, 10, 15, 20, 25, 50, 75, 100 of active ingredient for adjusting the symptoms of the dosage for the patient being treated. , 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, or 1000 milligrams. The compound can be administered in a regimen of 1 to 4 times daily, preferably once or twice daily. This dosage regimen can be adjusted to provide the optimal therapeutic response. However, the specific dose level and frequency of dosage for any particular patient can vary, and the activity of the particular compound used, the metabolic stability and time of action of that compound, age, weight, general health, sex, diet, administration It will be understood that it depends on a variety of factors including the mode and time of the, the rate of excretion, the drug combination, the severity of the particular disease and the host receiving treatment.

Thus, in some embodiments, the present disclosure comprises contacting at least one cell with at least one disclosed compound or at least one product of the disclosed method in an amount effective to antagonize mAChR M ₄ in at least one cell. It relates to a method of antagonizing the mAChR M ₄ receptor in at least one cell. In some embodiments, the cell is a mammal, eg, human. In some embodiments, cells are isolated from the subject prior to the contacting step. In some embodiments, the contact is through administration to a subject.

In some embodiments, the invention provides mAChR M in a subject comprising administering to the subject at least one product of the disclosed method or at least one disclosed compound at a dose and amount effective to antagonize the mAChR M ₄ receptor in the subject. _It relates to a method of antagonizing ₄ receptors. In some embodiments, the subject is a mammal, eg, human. In some embodiments, the mammal is diagnosed as requiring mAChR M ₄ antagonism prior to the administration step. In some embodiments, the mammal is diagnosed as requiring mAChR M ₄ antagonism prior to the administration step. In some embodiments, the method further comprises identifying a subject in need of mAChR M ₄ antagonism.

b. Muscarinic  Antagonism of acetylcholine receptors

In some embodiments, the present disclosure administers to a mammal a pharmaceutical composition comprising an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or at least one disclosed compound or a pharmaceutically acceptable salt thereof. It relates to a method of antagonizing mAChR M ₄ in a mammal comprising a step.

In some embodiments, antagonism of the muscarinic acetylcholine receptor reduces muscarinic acetylcholine receptor activity.

In some embodiments, the administered compound antagonizes mAChR M ₄ with an IC ₅₀ of less than about 10 μM, less than about 5 μM, less than about 1 μM, less than about 500 nM, or less than about 100 nM. In some embodiments, the administered compound antagonizes mAChR M ₄ with an IC ₅₀ of about 10 μM to about 1 nM, about 1 μM to about 1 nM, about 100 nM to about 1 nM, or about 10 nM to about 1 nM. Order.

In some embodiments, the mammal is a human. In some embodiments, the mammal is diagnosed as needing a reduction in muscarinic acetylcholine receptor activity prior to the administration step. In some embodiments, the method further comprises identifying a mammal that needs to reduce muscarinic acetylcholine receptor activity. In some embodiments, antagonism of muscarinic acetylcholine receptors treats disorders associated with muscarinic acetylcholine receptor activity in mammals. In some embodiments, the muscarinic acetylcholine receptor is mAChR M ₄ .

In some embodiments, antagonism of muscarinic acetylcholine receptors in mammals is associated with treatment of disorders associated with muscarinic receptor dysfunction, such as the disorders disclosed herein. In some embodiments, the muscarinic receptor is mAChR M ₄ .

In some embodiments, the present disclosure provides a method of antagonizing a muscarinic acetylcholine receptor in a cell comprising contacting the cell with an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof. In some embodiments, the cell is a mammal (eg, human). In some embodiments, cells are isolated from mammals prior to the contacting step. In some embodiments, the contact is through administration to a mammal.

c. Joint treatment method

The present disclosure further relates to administration of a mAChR M ₄ antagonist to improve treatment results, such as a selective mAChR M ₄ antagonist. That is, in some embodiments, the present disclosure relates to a co-treatment method comprising administering to an mammal an effective amount and an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

In some embodiments, administration improves treatment results in the context of cognitive or behavioral therapy. Administration linked to cognitive or behavioral therapy can be continuous or intermittent. Administration need not be concurrent with treatment, but may be before, during and / or after treatment. For example, cognitive or behavioral therapy can be given within 1, 2, 3, 4, 5, 6, 7 days before or after administration of the compound. As a further example, cognitive or behavioral therapy can be given within 1 week, 2 weeks, 3 weeks, or 4 weeks before or after administration of the compound. In still further examples, cognitive or behavioral therapy may be provided before or after administration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 half-life of the administered compound.

In some embodiments, administration can improve treatment results in the context of physical or occupational treatment. Administration linked with physical or occupational therapy can be continuous or intermittent. Administration need not be concurrent with treatment, but may be before, during and / or after treatment. For example, physical or occupational treatment can be given within 1, 2, 3, 4, 5, 6, 7 days before or after administration of the compound. As a further example, physical or occupational treatment can be given within 1 week, 2 weeks, 3 weeks, or 4 weeks before or after administration of the compound. In still further examples, physical or occupational treatment may be provided before or after administration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 half-life of the administered compound.

It is understood that the disclosed co-treatment methods can be used in conjunction with the disclosed compounds, compositions, kits and uses.

d. Combination treatment

In the methods of use described herein, the additional therapeutic agent (s) can be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, additional therapeutic agents or therapeutic agents can be administered in the same composition as the disclosed compounds. In other embodiments, there may be a time interval between the additional therapeutic agent and administration of the disclosed compounds. In some embodiments, administration of the disclosed compounds and additional therapeutic agents may allow administration of lower doses and / or less frequent intervals of other therapeutic agents. When used in combination with one or more other active ingredients, the compounds of the present invention and other active ingredients can each be used in lower doses than when used alone. Accordingly, the pharmaceutical composition of the present invention comprises containing one or more other active ingredients in addition to the compound of formula (I). The combination includes a compound of the present invention and one other active compound, as well as a combination of two or more other active compounds.

The disclosed compounds can be used as a single agent or in combination with one or more other drugs in the treatment, prevention, control, alleviation or reduction of risk of the above-mentioned diseases, disorders and conditions in which the compound or other drug has utility, wherein the drug The combination of drugs is safer or more effective than the drug alone. Other drug (s) can be administered simultaneously or sequentially with the compounds disclosed in amounts and by routes commonly used for this. When the disclosed compounds are used simultaneously with one or more other drugs, pharmaceutical compositions in unit dosage form containing these drugs and the disclosed compounds can be used. However, combination treatments can also be administered on overlapping schedules. It is also contemplated that a combination of one or more active ingredients and disclosed compounds may be more efficient than a single agent. Thus, when used in combination with one or more other active ingredients, the disclosed compounds and other active ingredients can each be used in lower doses than when used alone.

The pharmaceutical compositions and methods of the present invention may further include other therapeutically active compounds as described herein that are commonly applied in the treatment of the above-mentioned pathological diseases.

Such combinations include combinations of the disclosed compounds with one or more other active compounds as well as one other active compound. Likewise, the disclosed compounds can be used in combination with other drugs in which the disclosed compounds are used to prevent, treat, control, alleviate or reduce the risk of a useful disease or condition. These other drugs can be administered simultaneously or sequentially with the compounds of the present invention by routes and amounts commonly used for them. When the compounds of the present invention are used simultaneously with one or more other drugs, pharmaceutical compositions containing these other drugs in addition to the disclosed compounds are preferred. Thus, pharmaceutical compositions include those that also contain one or more other active ingredients in addition to the compounds of the present invention.

The weight ratio of the disclosed compounds to the second active ingredient can vary and will depend on the effective dose of each ingredient. Generally, each effective dose will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the disclosed compound to the other agent is generally from about 1000: 1 to about 1: 1000, preferably from about 200: 1 to about 1: It will be in the range of 200. Combinations of the compounds of the invention with other active ingredients will generally also be within the above-mentioned ranges, but in each case an effective dose of each active ingredient should be used.

In this combination, the disclosed compounds and other active agents can be administered individually or together. Additionally, administration of one element can be prior to, concurrent with, or after administration of another agent.

Thus, the disclosed compounds alone or in combination with other agents known to be beneficial to the indication or other drugs that affect the receptor or enzyme that increase the effectiveness, safety, convenience or reduce unwanted side effects or toxicity of the disclosed compounds. Can be used. The compounds and other agents can be administered concurrently or in fixed combinations.

In some embodiments, the compounds may be used in combination with any other agents used to treat the disorders described herein, such as standard management treatments for disorders likely to benefit from mAChR M ₄ antagonism such as the disorders described herein. You can. For example, in some embodiments, the compound is a Parkinson's syndrome drug (e.g., L-DOPA or carbidopa / levodopa), mGlu ₄ positive allosteric modulator, mGlu ₅ negative allosteric modulator, A ₂ A inhibitor , T-type calcium channel antagonist, VMAT2 inhibitor, muscle relaxant (e.g., baclofen), anticholinergics, antiemetic, typical or atypical neuroleptics (e.g., risperidone, ziprasidone, haloperidol, pimozide , Fluphenazine), antihypertensive agents (e.g. clonidine or guanfacin), tricyclic antidepressants (e.g. amitriptyline, butriptyline, clomipramine, desipramine, dosulepine, doxepin, Imipramine, iprindol, lofepramine, nortriptyline, protriptyline or trimipramine), agents that increase extracellular dopamine levels (e.g. amphetamine, methylphenidate or risdexamphetamine), Excessive daytime sleepiness Agents to be treated (e.g., sodium oxybate or arousal accelerators, such as armodafinyl or modafinil) and norepinephrine reuptake inhibitors (selective NRIs, e.g., atomoxetine and non-selective NRIs, e.g. , Bupropion).

e. Method of administration

The method of administration can include any number of ways of administering the disclosed composition. Dosages include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solids It may contain a dispersion or a dispersible powder. For the preparation of pharmaceutical compositions for oral administration, the formulation may be, for example, gum arabic, talc, starch, sugar (e.g., mannitol, methyl cellulose, lactose, etc.), gelatin, surfactant, magnesium stearate , Aqueous or non-aqueous solvents, paraffin derivatives, crosslinkers, dispersants, emulsifiers, lubricants, preservatives, flavoring agents (e.g. ethereal oils), solubility enhancers (e.g. benzyl benzoate or benzyl alcohol) or bio It can be mixed with commonly known and used adjuvants and excipients, such as utilization enhancers (eg Gelucire ^™ ). In pharmaceutical compositions, the formulations can also be dispersed in microparticles, such as nanoparticulate compositions.

For parenteral administration, the formulations can be dissolved or suspended in physiologically acceptable diluents, such as, for example, water, buffers, solubilizing or oil-free oils, surfactants, dispersants or emulsifiers. For example, as an oil, without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil can be used. More generally speaking, for parenteral administration, the formulations can be in the form of aqueous, lipid, oily or other types of solutions or suspensions, or even in the form of liposomes or nano-suspensions.

The term "parenterally" as used herein refers to a mode of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intra-articular injections and infusions.

5. Kit

In one aspect, the present disclosure provides a pharmaceutical composition comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, or at least one disclosed compound or a pharmaceutically acceptable salt thereof, and

(a) at least one agent known to increase mAChR M ₄ activity;

(b) at least one agent known to reduce mAChR M ₄ activity;

(c) at least one agent known to treat disorders associated with mAChR M ₄ , such as the disorders described herein; And

(d) instructions for administering the compound

It provides a kit comprising one or more of the.

In some embodiments, at least one disclosed compound and at least one agent are formulated together. In some embodiments, at least one disclosed compound and at least one agent are packaged together. Kits can also include compounds and / or products that are packaged together with other ingredients, formulated together and / or delivered together. For example, a drug manufacturer, drug reseller, physician, pharmacy, or pharmacist can provide a kit comprising the disclosed compounds and / or products and another ingredient for delivery to a patient.

The disclosed kits can be used in connection with the disclosed methods of use.

The kit may further include information, instructions, or both, that the use of the kit will provide treatment for diseases of mammals (especially humans). The information and instructions can be in the form of text, pictures, or both. Additionally or alternatively, the kit may contain a compound, composition, or both; And compounds, or compositions, preferably methods of application of those having the benefit of treating or preventing a disease in a mammal (eg, a human), information, instructions or both.

The compounds and processes of the invention will be better understood with reference to the following examples, which are intended as illustrations of the invention and are not limiting on the scope of the invention.

6. Example

All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer. ^{The 1} H chemical shift is reported as the δ value expressed in ppm of the downfield with the deuterium containing solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quadruple, dd = doublet of doublet, m = multiplet, ABq = AB quartet), coupling constant, integral. Reverse phase LCMS analysis was performed with the following parameters using a binary pump with a degasser, a high performance autosampler, a thermostatically controlled column compartment, a C18 column, an Agilent 1200 system consisting of a diode-array detector (DAD) and an Agilent 6150 MSD. . The gradient conditions were 5% to 95% acetonitrile with 0.1% TFA in water in 1.4 min. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 μm, 1.0 × 50 mm) at 0.5 ml / min while maintaining the column and solvent temperature at 55 ° C. The DAD was set to scan from 190 nm to 300 nm, and the signals used were 220 nm and 254 nm (both have a bandwidth of 4 nm). The MS detector consisted of an electrospray ionization source, and the low resolution mass spectrum was collected by scanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13 cycles / second and a peak width of 0.008 minutes. The dry gas flow rate was set at 300 ° C at 13 liters per minute and the nebulizer pressure at 30 psi. The capillary needle voltage was set at 3000 V, and the fragmenter voltage at 100 V. Data collection was performed using Agilent Chemstation and Analytical Studio Reviewer software.

The following examples and abbreviations used in the reaction schemes are as follows:

AcOH Acetic acid

BrettPhos-Pd-G3 Methanesulfonato (2-dicyclohexylphosphino-3,6-dimethoxy-2 ', 4', 6'-tri-i-propyl-1,1'-biphenyl) (2'-amino-1 , 1'-biphenyl-2-yl) palladium (II) (CAS number 1470372-59-8)

DCE 1,2-dichloroethane

DCM Dichloromethane

DIPEA N, N -diisopropylethylamine

DMF N , N -dimethylformamide

EtOAc Ethyl acetate

h or hr time

HATU 1- [bis (dimethylamino) methylene] -1 H -1,2,3-triazolo [4,5- b ] pyridinium 3-oxide hexafluorophosphate

IPA Isopropyl alcohol

LAH Lithium aluminum hydride

MeOH Methanol

NaBH (OAc) ₃ sodium triacetoxyborohydride

NMP N -methyl-2-pyrrolidone

PyClU 1- (chloro-1-pyrrolidinylmethylene) pyrrolidinium hexafluorophosphate

RP-HPLC Reverse phase high performance liquid chromatography

rt or r.t. Room temperature

RuPhos-Pd-G3 Methanesulfonato (2-dicyclohexylphosphino-2 ', 6'-di-i-propoxy-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2- Sun) Palladium (II) (CAS number 1445085-77-7)

SFC Supercritical fluid chromatography

THF Tetrahydrofuran

Example  1. 6- (2- Chloro -5- Fluorophenyl )- N -((6-((3- ( Trifluoromethyl ) Pyridin-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazine-3-amine (Compound 1))

tert -Butyl 1-(((6 -chloropyridazin- 3-yl) amino) methyl ) -6- azaspiro [2.5] octane -6-carboxylate. tert-Butyl 2- (aminomethyl) -6-azaspiro [2.5] octane-6-carboxylate (3.0 g, 12.5 mmol) was dissolved in t-BuOH (14 mL), DIPEA (6.5 mL, 37.4 mmol) ), Followed by 3,6-dichloropyridazine (4.65 g, 31.2 mmol). The resulting suspension was heated to 100 ° C. overnight, after which the reaction was cooled to rt and diluted with DCM and saturated NaHCO ₃ . The aqueous layer was extracted with DCM, and the organic extract was filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC, and the product containing fractions were extracted with DCM. The organic extract was dried over MgSO ₄ , filtered and concentrated to give the title compound as a white sponge solid (1.86 g, 42%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.16 (d, J = 9.2 Hz, 1H), 6.64 (d, J = 9.3 Hz, 1H), 4.74 (br, 1H), 3.65 (br, 2H), 3.47-3.35 (m, 2H), 3.26-3.20 (m, 2H), 1.69-1.62 (m, 1H), 1.57-1.51 (m, 1H), 1.46 (s, 9H), 1.40-1.35 (m, 1H) ), 1.17-1.13 (m, 1H), 1.05-0.98 (m, 1H), 0.63 (dd, J = 8.4, 4.7 Hz, 1H), 0.30 (t, J = 5.0 Hz, 1H). ES-MS [M + H] ⁺ = 353.2 .

tert -Butyl 1-(((6- (2 -chloro- 5- fluorophenyl ) pyridazine- 3-yl) amino) methyl ) -6-azaspiro [2.5] octane-6-carboxylate. Tert-butyl 1-(((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] octane-6-carboxylate (199 mg, 0.56 mmol) in a 5 ml microwave vial , 2-chloro-5-fluorophenylboronic acid (147 mg, 0.85 mmol), K ₂ CO ₃ (237 mg, 1.69 mmol) and RuPhos-Pd-G3 (24 mg, 0.03 mmol) were added. Then, a degassed mixture of 5: 1 1,4-dioxane / H ₂ O (2.5 mL) was added, and the resulting suspension was stirred at 120 ° C. for 30 minutes under microwave irradiation, after which the reaction mixture was rt. Cooled to and diluted with DCM and saturated NaHCO ₃ . The aqueous layer was extracted with DCM, and the organic extract was filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (hex / EtOAc) to give the title compound as a colorless oil (100 mg, 40%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.61 (d, J = 9.2 Hz, 1H), 7.47 (d, J = 9.1, 3.1 Hz, 1H), 7.40 (dd, J = 8.8, 5.0 Hz, 1H ), 7.06-7.01 (m, 1H), 6.69 (d, J = 9.3 Hz, 1H), 4.93 (br, 1H), 3.65 (br, 2H), 3.55-3.42 (m, 2H), 3.28-3.21 ( m, 2H), 1.71-1.65 (m, 1H), 1.58-1.52 (m, 1H), 1.46 (s, 9H), 1.43-1.38 (m, 1H), 1.18-1.13 (m, 1H), 1.10- 1.03 (m, 1H), 0.64 (dd, J = 8.4, 4.7 Hz, 1H), 0.32 (t, J = 5.0 Hz, 1H). ES-MS [M + H] ⁺ = 447.2.

N -((6- azaspiro [2.5] octan -1-yl) methyl ) -6- (2 -chloro- 5- fluorophenyl ) pyridazine- 3-amine. tert-Butyl 1-(((6- (2-chloro-5-fluorophenyl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] octane-6-carboxylate (100 mg , 0.22 mmol) was dissolved in 1,4-dioxane (2 mL). Next, 4M HCl (2 mL) in 1,4-dioxane solution was added dropwise. The resulting mixture was stirred at rt for 30 minutes, after which the solvent was removed under reduced pressure, and the resulting white solid was dried under vacuum and used as the HCl salt as the title compound without further purification. ES-MS [M + H] ⁺ = 347.0.

6- (2 -Chloro- 5- fluorophenyl ) -N -((6-((3- ( trifluoromethyl ) pyridin-2-yl) methyl ) -6-azaspiro [2.5] octane-1- 1) Methyl) pyridazine-3-amine (Compound 1). N -((6-azaspiro [2.5] octan-1-yl) methyl) -6- (2-chloro-5-fluorophenyl) pyridazine-3-amine hydrochloride salt (11 mg, 0.028 mmol) Suspended in DCM (1 mL), 3- (trifluoromethyl) pyridine-2-carbaldehyde (24 mg, 0.14 mmol) was added, allowed to stir for 5 min at rt, and then sodium triacetoxybo Rohydride (30 mg, 0.14 mmol) was added. The resulting solution was stirred at rt overnight, after which the reaction mixture was quenched with saturated NaHCO ₃ and extracted with 3: 1 chloroform / IPA. The organic extract was filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC, and the fraction containing the product was basified with saturated NaHCO ₃ and extracted with 3: 1 chloroform / IPA. The organic extract was filtered through a phase separator and concentrated to give the title compound as a colorless oil (6.2 mg, 44%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.80 (dd, J = 4.6, 0.8 Hz, 1H), 7.95 (dd, J = 8.0, 1.2 Hz, 1H), 7.61 (d, J = 9.3 Hz, 1H ), 7.48 (dd, J = 9.2, 3.1 Hz, 1H), 7.41 (dd, J = 8.8, 5.0 Hz, 1H), 7.31 (dd, J = 7.8, 4.8 Hz, 1H), 7.07-7.02 (m, 1H), 6.68 (d, J = 9.3 Hz, 1H), 4.83 (t, J = 4.6 Hz, 1H), 3.83 (s, 2H), 3.52-3.41 (m, 2H), 2.67-2.62 (m, 2H ), 2.50-2.45 (m, 2H), 1.83-1.78 (m, 1H), 1.69-1.65 (m, 1H), 1.49-1.46 (m, 1H), 1.25-1.20 (m, 1H), 1.05-0.97 (m, 1H), 0.61 (dd, J = 8.4, 4.6 Hz, 1H), 0.28 (t, J = 4.9 Hz, 1H). ES-MS [M + H] ⁺ = 506.2.

Example  2. N -((6- (3,3- Dimethylbutyl ) -6- Azaspiro [2.5] octane -1 day) methyl ) -6- (4-fluorophenyl) pyridazine-3-amine (Compound 2)

6 -Chloro - N -((6- (3,3- dimethylbutyl ) -6- azaspiro [2.5] octan -1-yl) methyl ) pyridazine- 3-amine. tert-butyl 1-(((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] octane-6-carboxylate (prepared as described in Example 1) (1.34 g, 3.80 mmol) was dissolved in 1,4-dioxane (15 mL) and 4 M HCl (15 mL) in dioxane solution was added dropwise. The resulting turbid solution was stirred at rt for 30 minutes, after which the solvent was concentrated to a white solid, which was dried under vacuum and used as an HCl salt without further purification. The previously mentioned HCl salt (1.10 g, 3.80 mmol) was suspended in DCM (20 mL), followed by 3,3-dimethylbutyraldehyde (1.14 g, 11.39 mmol) followed by sodium triacetoxyborohydride ( 2.41 g, 11.39 mmol) was added dropwise. The resulting suspension was stirred at rt for 6 h, after which the reaction was cooled to 0 ° C. and quenched with saturated NaHCO ₃ . The aqueous layer was extracted with DCM and 3: 1 chloroform / IPA. The organic extract was dried over MgSO ₄ , the solvent was filtered and concentrated to give the title compound as a yellow oil, which was used directly without further purification (1.28 g, 100%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.12 (d, J = 9.3 Hz, 1H), 6.68 (d, J = 9.3 Hz, 1H), 5.05 (br, 1H), 3.41-3.36 (m, 2H ), 2.68 (br, 2H), 2.45-2.41 (m, 4H), 1.80-1.38 (m, 6H), 1.00-0.93 (m, 1H), 0.89 (s, 9H), 0.57 (dd, J = 8.4 , 4.7 Hz, 1H), 0.24 (t, J = 4.9 Hz, 1H). ES-MS [M + H] ⁺ = 337.3.

N -((6- (3,3- dimethylbutyl ) -6- azaspiro [2.5] octan -1-yl) methyl ) -6- (4- fluorophenyl ) pyridazine-3-amine (Compound 2) . 6-chloro- N -((6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazine-3-amine (20 mg, 0.06 mmol), K ₂ CO ₃ (25 mg, 0.18 mmol), 4-fluorophenylboronic acid (10 mg, 0.07 mmol) and RuPhos-Pd-G3 (5 mg, 0.006 mmol) were combined in a sealed vial, followed by a 5: 1 1 A solution of, 4-dioxane / H ₂ O (1.2 mL, degassed) was added via syringe. The resulting suspension was stirred for 2 h at 100 ° C. under an inert atmosphere, after which the reaction was cooled to rt and diluted with saturated NaHCO ₃ and 3: 1 chloroform / IPA. The aqueous layer was extracted with 3: 1 chloroform / IPA, and the organic extract was filtered through a phase separator. The solvent was concentrated and the crude residue was purified by RP-HPLC. The product containing fraction was basified with saturated NaHCO ₃ and extracted with 3: 1 chloroform / IPA. The solvent was filtered through a phase separator and concentrated to give the title compound as a colorless oil (2.7 mg, 11%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.95-7.91 (m, 2H), 7.57 (d, J = 9.3 Hz, 1H), 7.18-7.12 (m, 2H), 6.74 (d, J = 9.3 Hz , 1H), 4.78 (t, J = 4.6 Hz, 1H), 3.48 (t, J = 6.7 Hz, 2H), 2.67 (br, 2H), 2.45-2.40 (m, 4H), 1.81-1.25 (m, 6H), 1.06-0.99 (m, 1H), 0.91 (s, 9H), 0.61 (dd, J = 8.4, 4.6 Hz, 1H), 0.29 (t, J = 5.0 Hz, 1H). ES-MS [M + H] ⁺ = 397.4.

Example  3. N -((6-((( One R ,2 R ,4 S ) -7- Oxabicyclo [2.2.1] heptane -2 days) methyl ) -6-Azaspiro [2.5] octan-1-yl) methyl) -6- (1,3-dimethyl-1 H -Pyrazol-4-yl) pyridazin-3-amine (Compound 3)

tert -butyl 1-(((6- (1,3-dimethyl-1 H - pyrazol -4-yl) pyridazine- 3-yl) amino) methyl ) -6-azaspiro [2.5] octane-6- Carboxylate. tert-butyl 1-(((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] octane-6-carboxylate (prepared as described in Example 1) (68 Mg, 0.19 mmol), 1,3-dimethyl-1 H -pyrazole-4-boronic acid pinacol ester (51 mg, 0.23 mmol), K ₂ CO ₃ (81 mg, 0.58 mmol) and RuPhos-Pd-G3 (8 mg, 0.010 mmol) was dissolved in 5: 1 1,4-dioxane / H ₂ O (2.4 mL, degassed), and the resulting solution was heated in a sealed flask at 100 ° C. for 1 h, then The reaction mixture was cooled to rt and diluted with saturated NaHCO ₃ and DCM. The aqueous layer was extracted with DCM (3x), and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (12% to 100% EtOAc / hexane to 0% to 10% MeOH / EtOAc) to give the title compound as a colorless oil (35 mg, 45%). ES-MS [M + H] ⁺ = 413.3.

N -((6- Azaspiro [2.5] octane -1-yl) methyl ) -6- (1,3-dimethyl- 1H - pyrazol -4-yl) pyridazine- 3-amine dihydrochloride . tert-butyl 1-(((6- (1,3-dimethyl-1 H -pyrazol-4-yl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] octane-6- Carboxylate (35 mg, 0.086 mmol) was dissolved in 1,4-dioxane (1 mL) and 4 M HCl (1 mL) in dioxane solution was added dropwise. The resulting solution was stirred at rt for 30 minutes, after which the solvent was concentrated to a white solid, which was dried under vacuum and used as an HCl salt without further purification. ES-MS [M + H] ⁺ = 313.3.

(( 1 R , 2 S , 4 S ) -7 -oxabicyclo [2.2.1] heptan -2-yl) (1-(((6- (1,3-dimethyl-1 H -pyrazole-4 -Yl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] octane-6-yl) methanone .. N -((6-azaspiro [2.5] octan-1-yl) methyl ) -6- (1,3-dimethyl-1 H -pyrazol-4-yl) pyridazine-3-amine dihydrochloride (33 mg, 0.086 mmol) was dissolved in DMF (1 mL), followed by rac- (1 R , 2 S , 4 S ) -7-oxabicyclo [2.2.1] heptan-2-carboxylic acid (18 mg, 0.13 mmol) followed by DIPEA (0.045 mL, 0.26 mmol) and HATU (49 mg , 0.13 mmol). The resulting solution was stirred at rt for 4h, after which the reaction was quenched with saturated NaHCO ₃ and the aqueous layer was extracted with 3: 1 chloroform / IPA. The solvent was filtered through a phase separator and concentrated, and the crude residue was purified by RP-HPLC. The product containing fraction was basified with saturated NaHCO ₃ and extracted with 3: 1 chloroform / IPA. The solvent was filtered through a phase separator and concentrated to give the title compound as a colorless oil (17.3 mg, 46%). ES-MS [M + H] ⁺ = 437.5.

N -((6-((( 1 R , 2 R , 4 S ) -7- oxabicyclo [2.2.1] heptan -2-yl) methyl ) -6- azaspiro [2.5] octan -1-yl ) Methyl) -6- (1,3-dimethyl- 1H -pyrazol-4-yl) pyridazine-3-amine (Compound 3). ((1 R , 2 S , 4 S ) -7-oxabicyclo [2.2.1] heptan-2-yl) (1-(((6- (1,3-dimethyl-1 H -pyrazole-4 -Yl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] octane-6-yl) methanone (17.3 mg, 0.04 mmol) was dissolved in THF (1 mL), to 0 ° C Cooled. Then, LAH (0.079 ml, 0.08 mmol, 1.0 M in THF) was added dropwise, and the resulting solution was stirred at 0 ° C. for 30 minutes. The reaction was quenched by slow addition of saturated NaHCO ₃ and the aqueous layer was extracted with DCM and 3: 1 chloroform / IPA. The organic extract was filtered through a phase separator and concentrated, and the crude residue was purified by RP-HPLC. The product containing fraction was basified with saturated NaHCO ₃ and extracted with 3: 1 chloroform / IPA. The solvent was filtered through a phase separator and concentrated to give the title compound as a colorless oil, which solidified upon standing (1.0 mg, 6%). ES-MS [M + H] ⁺ = 423.5.

Example  4. 6- (1,4-dimethyl-1H- Pyrazole -5-day) -N-((6- (2- ( Tetrahydrofuran -2-yl) ethyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazine-3-amine (Compound 4))

tert -butyl 1-(((6- (1,4-dimethyl- 1H - pyrazol -5-yl) pyridazine- 3-yl) amino) methyl ) -6-azaspiro [2.5] octane-6- Carboxylate. tert-butyl 1-(((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] octane-6-carboxylate (prepared as described in Example 1) (133 Mg, 0.38 mmol), 1,4-dimethylpyrazole-5-boronic acid pinacol ester (125 mg, 0.56 mmol), K ₂ CO ₃ (158 mg, 1.13 mmol) and RuPhos-Pd-G3 (16 mg, 0.019 mmol) was dissolved in 5: 1 1,4-dioxane / H ₂ O (3 mL, degassed), and the resulting solution was heated at 120 ° C. for 20 minutes under microwave irradiation, after which the reaction mixture was Cool to rt and diluted with saturated NaHCO ₃ and DCM. The aqueous layer was extracted with DCM (3x), and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (12% to 100% EtOAc / hexane to 0% to 10% MeOH / EtOAc) to give the title compound as a colorless oil (37 mg, 24%). ES-MS [M + H] ⁺ = 413.2.

N - ((6- azaspiro [2.5] octane-1-yl) methyl) -6- (1,4-dimethyl -1 H - pyrazol-5-yl) pyridazin-3-amine dihydrochloride. tert-butyl 1-(((6- (1,4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] octane-6-car Foxylate (64 mg, 0.16 mmol) was dissolved in 1,4-dioxane (1 mL) and 4 M HCl (1 mL) in dioxane solution was added dropwise. The resulting solution was stirred at rt for 1 h, after which the solvent was concentrated to a white solid, which was dried under vacuum and used as an HCl salt without further purification. ES-MS [M + H] ⁺ = 313.3

6- (1,4-dimethyl-1H- pyrazol -5-yl) -N-((6- (2- ( tetrahydrofuran- 2-yl) ethyl) -6-azaspiro [2.5] octane-1 -Yl) methyl) pyridazine-3-amine (Compound 4). N -((6-azaspiro [2.5] octan-1-yl) methyl) -6- (1,4-dimethyl- 1H -pyrazol-5-yl) pyridazine-3-amine dihydrochloride (12 Mg, 0.031 mmol) was suspended in DCM (1 mL) and 2- (2-bromoethyl) oxolane (11 mg, 0.062 mmol) was added followed by K ₂ CO ₃ (8.7 mg, 0.062 mmol). The resulting suspension was stirred at rt for 4 h, after which the reaction was quenched with saturated NaHCO ₃ and the aqueous layer was extracted with 3: 1 chloroform / IPA. The solvent was filtered through a phase separator and concentrated, and the crude residue was purified by RP-HPLC. The product containing fraction was basified with saturated NaHCO ₃ and extracted with 3: 1 chloroform / IPA. The solvent was filtered through a phase separator and concentrated to give the title compound as a white solid (2 mg, 16%). ES-MS [M + H] ⁺ = 411.4.

Example 5. Chiral separation

30% isocratic gradient with MeOH as tert-butyl 1-(((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] octane-6-carboxylate as a co-solvent Separated into individual enantiomers via preparative SFC purification (CHIRALPAK IC 20 x 250 mm column). Retention time of the early eluting enantiomer O : 7.03 min (peak 1), retention time of the last eluting enantiomer P : 7.65 min (peak 2). Peak 1 is a higher affinity enantiomer. X-ray crystallographic analysis showed that compound O had (R) -stereochemistry in cyclopropane as shown in FIG. 1.

Example  6. N -(6- (1,4-dimethyl-1 H - Pyrazole -5 days) Pyridazine -3-day) -6- (3,3- Dimethylbutyl ) -6-Azaspiro [2.5] octane-1-carboxamide. (Compound 5)

tert -Butyl 1-((6 -chloropyridazine- 3-yl) carbamoyl ) -6- azaspiro [2.5] octane -6-carboxylate. 6-Boc-6-azaspiro [2.5] octane-1-carboxylic acid (100 mg, 0.39 mmol) and 3-amino-6-chloropyridazine (101 mg, 0.78 mmol) were added with DCE (3 mL) and DIPEA. (0.14 mL, 0.78 mmol) and PyClU (261 mg, 0.78 mmol) was added. The resulting suspension was heated to 110 ° C. for 20 minutes by microwave irradiation, after which the reaction was cooled to rt and diluted with DCM and H ₂ O. The aqueous layer was extracted with DCM, and the organic extract was filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (hexane / EtOAc) to give the title compound as a white solid (61 mg, 43%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 10.4 (br, 1H), 8.60 (d, J = 9.4 Hz, 1H), 7.51 (d, J = 9.3 Hz, 1H), 3.58-3.48 (m, 2H ), 3.42-3.35 (m, 1H), 3.25-3.19 (m, 1H), 2.18 (dd, J = 7.6, 5.6 Hz, 1H), 1.75 (t, J = 5.7 Hz, 2H), 1.59-1.53 ( m, 1H), 1.48-1.46 (m, 1H), 1.44 (s, 9H), 1.36 (t, J = 4.9 Hz, 1H), 1.08 (dd, J = 7.6, 4.5 Hz, 1H). ES-MS [M + H] ⁺ = 367.2.

tert -butyl 1-((6- (1,4-dimethyl-1 H - pyrazol -5-yl) pyridazine- 3-yl) carbamoyl ) -6-azaspiro [2.5] octane-6-car Succinate. tert-butyl 1-((6-chloropyridazin-3-yl) carbamoyl) -6-azaspiro [2.5] octane-6-carboxylate (61 mg, 0.17 mmol), 1,4-dimethylpyra Sol-5-boronic acid pinacol ester (44 mg, 0.20 mmol), K ₂ CO ₃ (70 mg, 0.50 mmol) and RuPhos-Pd-G3 (7 mg, 0.008 mmol) were combined in a sealed vial, 5: 1,4-dioxane / H ₂ O solution of 1 (1.2 mL, degassed) was added. The resulting suspension was stirred for 1 h at 100 ° C. under an inert atmosphere, after which the reaction mixture was cooled to rt and diluted with H ₂ O. The aqueous layer was extracted with DCM, and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (hex / EtOAc) to give the title compound as a colorless oil (55 mg, 78%). ES-MS [M + H] ⁺ = 427.2.

N- (6- (1,4- dimethyl- 1 H - pyrazol -5-yl) pyridazine- 3-yl) -6- (3,3- dimethylbutyl ) -6 - azaspiro [2.5] octane -1-carboxamide (Compound 5). tert-butyl 1-((6- (1,4-dimethyl- 1H -pyrazol-5-yl) pyridazin-3-yl) carbamoyl) -6-azaspiro [2.5] octane-6-car Foxylate (55 mg, 0.13 mmol) was dissolved in 1,4-dioxane (1 mL). Next, 4 M HCl (1 mL) in 1,4-dioxane solution was added dropwise. The resulting mixture was stirred at rt for 1 h, after which the solvent was removed under reduced pressure, and the resulting white solid was dried under vacuum and used as an HCl salt without further purification. The previously mentioned HCl salt (17 mg, 0.043 mmol) was suspended in DCM (1 mL), 3,3-dimethylbutyraldehyde (22 mg, 0.22 mmol) was added and allowed to stir at rt for 5 min. , After which sodium triacetoxyborohydride (46 mg, 0.22 mmol) was added. The resulting solution was stirred at rt overnight, after which the reaction mixture was quenched with H ₂ O and extracted with DCM. The organic extract was filtered through a phase separator and concentrated. The crude residue was purified by RP-HPLC, and the fraction containing the product was basified with saturated NaHCO ₃ and extracted with 3: 1 chloroform / IPA. The organic extract was filtered through a phase separator and concentrated to give the title compound as a colorless oil (7.6 mg, 43%). ES-MS [M + H] ⁺ = 411.4.

Example  7. N -[[6- (3,3- Dimethylbutyl ) -6- Azaspiro [2.5] octane -2 days] methyl ] -5- (1,3-dimethylpyrazol-4-yl) pyridin-2-amine (Compound 6)

tert -Butyl 1-(((5- bromopyridin-2 -yl) amino) methyl ) -6- azaspiro [2.5] octane -6-carboxylate. tert-Butyl 1- (aminomethyl) -6-azaspiro [2.5] octane-6-carboxylate (150 mg, 0.62 mmol) and 5-bromo-2-fluoropyridine (275 mg, 1.56 mmol) It was dissolved in NMP (1.5 mL) in a 2 mL microwave vial. DIPEA (0.33 mL, 1.87 mmol) was then added, and the resulting solution was heated at 180 ° C. for 1 h under microwave irradiation, after which the reaction mixture was purified directly by RP-HPLC, 3: 1 chloroform / IPA. It was extracted with. The organic extract was dried over MgSO ₄ , filtered and concentrated to give the title compound as a colorless oil (125 mg, 50%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 8.10 (d, J = 2.4 Hz, 1H), 7.47 (dd, J = 8.8, 2.5 Hz, 1H), 6.29 (d, J = 8.8 Hz, 1H), 4.51 (br, 1H), 3.64 (br, 2H), 3.27-3.21 (m, 4H), 1.68-1.61 (m, 1H), 1.56-1.49 (m, 1H), 1.46 (s, 9H), 1.39- 1.35 (m, 1H), 1.18-1.13 (m, 1H), 1.01-0.94 (m, 1H), 0.61 (dd, J = 8.4, 4.7 Hz, 1H), 0.27 (t, J = 4.9 Hz, 1H) . ES-MS [M + H] ⁺ = 396.4.

tert -butyl 1-(((5- (1,3-dimethyl-1 H - pyrazol -4-yl) pyridin-2-yl) amino) methyl ) -6-azaspiro [2.5] octane-6-car Succinate. tert-butyl 1-(((5-bromopyridin-2-yl) amino) methyl) -6-azaspiro [2.5] octane-6-carboxylate (51 mg, 0.13 mmol), 1,3-dimethyl -1 H -pyrazole-4-boronic acid pinacol ester (34 mg, 0.15 mmol), K ₂ CO ₃ (54 mg, 0.39 mmol) and RuPhos-Pd-G3 (5 mg, 0.006 mmol) 5: 1 In 1,4-dioxane / H ₂ O (2.4 mL, degassed), the resulting solution was heated in a sealed flask at 100 ° C. for 1 h, after which the reaction mixture was cooled to rt, saturated NaHCO ₃ and DCM. The aqueous layer was extracted with DCM (3x), and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (12% to 100% EtOAc / hexane to 0% to 10% MeOH / EtOAc) to give the title compound as a slightly brown oil (48 mg, 90%). ES-MS [M + H] ⁺ = 412.3.

N -((6- Azaspiro [2.5] octane -1-yl) methyl ) -5- (1,3- dimethyl- 1 H - pyrazol -4-yl) pyridin-2-amine dihydrochloride . tert-butyl 1-(((5- (1,3-dimethyl-1H-pyrazol-4-yl) pyridin-2-yl) amino) methyl) -6-azaspiro [2.5] octane-6-carboxyl Rate (48 mg, 0.12 mmol) was dissolved in 1,4-dioxane (1 mL) and 4 M HCl (1 mL) in dioxane solution was added dropwise. The resulting solution was stirred at rt for 30 minutes, after which the solvent was concentrated to a brown solid, which was dried under vacuum and used as an HCl salt without further purification. ES-MS [M + H] ⁺ = 312.3.

N -[[6- (3,3- dimethylbutyl ) -6- azaspiro [2.5] octan -2-yl] methyl ] -5- (1,3- dimethylpyrazol -4-yl) pyridin-2- Amines (Compound 6). N -((6-azaspiro [2.5] octan-1-yl) methyl) -5- (1,3-dimethyl-1H-pyrazol-4-yl) pyridin-2-amine dihydrochloride (15 mg, 0.039 mmol) was suspended in DCM (1 mL), followed by 3,3-dimethylbutyraldehyde (19 mg, 0.19 mmol) followed by sodium triacetoxyborohydride (41 mg, 0.19 mmol). The resulting suspension was stirred at rt for 5 h, after which time the reaction was quenched with saturated NaHCO ₃ . The aqueous layer was extracted with 3: 1 chloroform / IPA (3x). The organic extract was filtered through a phase separator and concentrated, and the crude residue was purified by RP-HPLC. The product containing fraction was basified with saturated NaHCO ₃ and extracted with 3: 1 chloroform / IPA. The organic extract was filtered through a phase separator and concentrated to give the title compound as a colorless oil (3.4 mg, 22%). ES-MS [M + H] ⁺ = 396.6.

The compounds listed in Table 1 were prepared analogously to the compounds described above with suitable starting materials. In Table 1, the “Reaction Scheme (s)” column represents the general scheme used to prepare the compounds, where the schemes are shown in the Detailed Description section.

[Table 1]

Example  8. 6- (3,3- Difluoropyrrolidine -1-yl) -N-((6- (3,3- Dimethylbutyl ) -6- Ah Jaspyro [2.5] octan-1-yl) methyl) pyridazine-3-amine (Compound 75)

6-chloro-N-((6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazine-3-amine (24 mg, 0.071 mmol) and 3, 3-Difluoropyrrolidine hydrochloride (51 mg, 0.36 mmol) was combined in a microwave vial, NMP (1 mL), then DIPEA (0.062 mL, 0.36 mmol) was added. The reaction mixture was heated at 200 ° C. for 1 h under microwave irradiation, after which the reaction mixture was purified directly by RP-HPLC. The product containing fraction was basified with saturated NaHCO ₃ and extracted with 3: 1 chloroform / IPA. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a slightly orange oil (12.3 mg, 42%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.67-6.61 (m, 2H), 4.13 (t, J = 4.8 Hz, 1H), 2.84 (t, J = 13.3 Hz, 2H), 3.66 (t, J = 7.2 Hz, 2H), 3.40-3.36 (m, 2H), 2.67 (br, 2H), 2.53-2.42 (m, 6H), 1.80-1.49 (m, 3H), 1.47-1.43 (m, 2H), 1.32 (br, 1H), 1.03-0.96 (m, 1H), 0.90 (s, 9H), 0.55 (dd, J = 8.4, 4.6 Hz, 1H), 0.23 (t, J = 4.9 Hz, 1H). [M + H] + = 408.3.

Example  9. 6- (1,4-dimethyl-1H- Pyrazole -5-yl) -N-((6- (3,3- Dimethylbutyl ) -6- Keep it up Spiro [2.5] octan-1-yl) methyl) -N-methylpyridazine-3-amine (Compound 76))

tert -Butyl 1-(((6 -chloropyridazin- 3-yl) ( methyl ) amino) methyl ) -6- azaspiro [2.5] octane -6-carboxylate . Tert-butyl 1-(((6-chloropyridazin-3-yl) amino) methyl) -6-azaspiro [2.5] octane-6-carboxylate (58 mg, 0.16 mmol) in DMF (1 mL) To the solution of was added sodium hydride (7.8 mg, 0.33 mmol, 60% dispersion in mineral oil) at 0 ° C. and the resulting mixture was stirred for 5 minutes. Then iodomethane (3 μl, 0.25 mmol) was added, and the resulting solution was stirred at 0 ° C. for 1 h, after which the reaction mixture was diluted with DCM and saturated NaHCO ₃ . The aqueous layer was extracted with DCM, and the combined organic extracts were passed through a phase separator and concentrated under reduced pressure. The crude residue was purified by column chromatography (hex / EtOAc) to give the title compound (37 mg, 62%). [M + H] + = 367.2.

tert -butyl 1-(((6- (1,4- dimethyl- 1H- pyrazol -5-yl) pyridazine- 3-yl) ( methyl ) amino) methyl) -6-azaspiro [2.5] octane- 6-carboxylate. tert-butyl 1-(((6-chloropyridazin-3-yl) (methyl) amino) methyl) -6-azaspiro [2.5] octane-6-carboxylate (37 mg, 0.10 mmol), 1, 4-Dimethylpyrazole-5-boronic acid pinacol ester (40 mg, 0.18 mmol), K ₂ CO ₃ (42 mg, 0.30 mmol) and BrettPhos-Pd-G3 (4.6 mg, 0.005 mmol) were combined in a microwave vial. , 5: 1 1,4-dioxane / H ₂ O solution (1 mL, degassed) was added under an inert atmosphere. The resulting mixture was heated at 120 ° C. for 20 minutes under microwave irradiation, after which the reaction mixture was diluted with DCM and saturated NaHCO ₃ . The aqueous layer was extracted with DCM, and the combined organic extracts were passed through a phase separator and concentrated under reduced pressure. The crude residue was purified by column chromatography (hexane / EtOAc) to give the title compound as a yellow oil (32 mg, 74%). [M + H] + = 427.4.

6- (1,4- Dimethyl- 1H- pyrazol -5-yl) -N-((6- (3,3- dimethylbutyl ) -6- azaspiro [2.5] octan -1-yl) methyl)- N-methylpyridazin-3-amine. tert-butyl 1-(((6- (1,4-dimethyl-1H-pyrazol-5-yl) pyridazin-3-yl) (methyl) amino) methyl) -6-azaspiro [2.5] octane- 6-Carboxylate (32 mg, 0.074 mmol) was dissolved in 1,4-dioxane (1 mL) and 4 M HCl (1 mL) in dioxane solution was added dropwise. The resulting solution was stirred at rt for 1 h, after which the solvent was concentrated under reduced pressure to give the HCl salt, which was used directly without further purification. HCl salt (30 mg, 0.074 mmol) was suspended in DCM (1 mL), 3,3-dimethylbutyraldehyde (37 mg, 0.37 mmol) followed by sodium triacetoxyborohydride (79 mg, 0.37 mmol) ) Was added. After stirring at rt overnight, the reaction mixture was heated to 55 ° C., stirred overnight, then AcOH (3 drops) was added and stirred overnight. The reaction mixture was cooled to rt and diluted with 3: 1 chloroform / IPA and saturated NaHCO ₃ . The aqueous layer was extracted with 3: 1 chloroform / IPA. The combined organic extracts were filtered through a phase separator and concentrated, and the crude residue was purified by RP-HPLC. The product containing fraction was basified with saturated NaHCO ₃ and extracted with 3: 1 chloroform / IPA. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a colorless oil (9.3 mg, 30%). [M + H] + = 411.5.

Example  10. 1-(((6- (2- Chloro -5- Fluorophenyl ) Pyridazine -3 days) Oxy ) methyl ) -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octane (Compound 77)

tert -Butyl 1-(((6 -chloropyridazin- 3-yl) oxy ) methyl ) -6- azaspiro [2.5] octane -6-carboxylate. tert-Butyl 1- (hydroxymethyl) -6-azaspiro [2.5] octane-6-carboxylate (466 mg, 1.93 mmol) was dissolved in THF (10 mL), NaH (93 mg, 3.86 mmol, 60% dispersion in mineral oil) was added at 0 ° C. After stirring for 5 minutes, 3,6-dichloropyridazine (432 mg, 2.90 mmol) was added. The resulting solution was warmed to rt, stirred overnight, and then the reaction mixture was diluted with DCM and H ₂ O. The aqueous layer was extracted with DCM, and the combined organic extracts were filtered through a phase separator and concentrated. The crude residue was purified by column chromatography (hex / EtOAc) to give the title compound as a white solid (541 mg, 79%). [M + H-Boc] + = 254.4.

tert -Butyl 1-((((6- (2 -chloro- 5- fluorophenyl ) pyridazine- 3-yl) oxy ) methyl ) -6-azaspiro [2.5] octane-6-carboxylate. tert-Butyl 1-(((6-chloropyridazin-3-yl) oxy) methyl) -6-azaspiro [2.5] octane-6-carboxylate (541 mg, 1.53 mmol), 2-chloro-5 -Fluorophenylboronic acid (320 mg, 1.83 mmol), K ₂ CO ₃ (643 mg, 4.59 mmol) and RuPhos-Pd-G3 (128 mg, 0.15 mmol) were combined in a microwave vial, 5: 1 1, 4-Dioxane / H ₂ O solution (12 mL, degassed) was added under an inert atmosphere. The resulting mixture was heated at 120 ° C. for 20 minutes under microwave irradiation, after which the reaction mixture was diluted with DCM and saturated NaHCO ₃ . The aqueous layer was extracted with DCM, and the combined organic extracts were dried over MgSO ₄ . The solvent was filtered, concentrated under reduced pressure, and the crude residue was purified by column chromatography (hex / EtOAc) to give the title compound as a white foamy solid (290 mg, 42% (89% purity)). [M + H-Boc] + = 348.2.

1-(((6- (2 -chloro- 5- fluorophenyl ) pyridazine- 3-yl) oxy ) methyl ) -6- (3,3- dimethylbutyl ) -6-azaspiro [2.5] octane. tert-butyl 1-(((6- (2-chloro-5-fluorophenyl) pyridazin-3-yl) oxy) methyl) -6-azaspiro [2.5] octane-6-carboxylate (290 mg , 0.65 mmol) was dissolved in 1,4-dioxane (5 mL), and 4 M HCl (4 mL) in dioxane solution was added dropwise. The resulting solution was stirred at rt for 1 h, after which the solvent was concentrated under reduced pressure to give the HCl salt, which was used directly without further purification. The HCl salt was suspended in DCM (1 mL) and 3,3-dimethylbutyraldehyde (27 mg, 0.27 mmol) was added, followed by sodium triacetoxyborohydride (57 mg, 0.27 mmol). After stirring at rt overnight, the reaction mixture was quenched with saturated NaHCO ₃ and the aqueous layer was extracted with 3: 1 chloroform / IPA. The combined organic extracts were filtered through a phase separator and concentrated, and the crude residue was purified by RP-HPLC. The product containing fraction was basified with saturated NaHCO ₃ and extracted with 3: 1 chloroform / IPA. The combined organic extracts were filtered through a phase separator and concentrated to give the title compound as a colorless oil (4.2 mg, 18%). [M + H] + = 432.4.

The compounds described in Table 1.1 were prepared analogously to the compounds described above with suitable starting materials. In Table 1.1, the "Reaction Scheme (s)" column represents the general scheme used to prepare the compounds, where the schemes are shown in the Detailed Description section.

TABLE 1.1

Example 11. Biological activity

A. Cell line expressing muscarinic acetylcholine receptor

Human, rat or mouse M ₄ cDNA was transfected with Chinese hamster ovary (CHO-K1) cells purchased from the American Type Culture Collection using Lipofectamine2000 with the chimeric G protein G _qi5 . Ham F-12 medium containing M ₄ / G _qi5 / CHO cells 10% heat inactivated fetal bovine serum (FBS), 20 mM HEPES, 500 μg / ml G418 sulfate and 200 μg / ml hygromycin B Grown in.

B. Cell-based function analysis of muscarinic acetylcholine receptor activity

For high throughput measurements of agonist-induced increase in intracellular calcium, CHO-K1 cells stably expressing muscarinic receptors were cultured in a Greiner 384 well assay wall tissue culture (TC) treated transparent bottom plate (VWR). Plated in growth medium without G418 and hygromycin at 15,000 cells / 20 μl / well. Cells were incubated overnight at 37 ° C. and 5% CO ₂ . The next day, cells were washed with assay buffer using ELX 405 (BioTek); The final volume was then aspirated to 20 μl. Next, fluoro-4 / acetoxymethyl ester (Invitrogen (California) prepared as 2.3 mM stock in DMSO, mixed with 10% (w / v) Pluronic F-127 in a 1: 1 ratio and diluted in assay buffer. 20 μl of a 2.3 μM stock of the main Carlsbad)) was added to the wells, and the cell plate was incubated at 37 ° C. and 5% CO ₂ for 50 minutes. The dye was removed by washing with ELX 405 and the final volume was aspirated to 20 μl. Compound master plates were formatted in a 10-point concentration-response curve (CRC) format (1: 3 dilution) in 100% DMSO at a starting concentration of 10 or 1 mM using a BRAVO liquid handler (Agilent). . The test compound CRC is then transferred to a daughter plate (240 nL) using an Echo Acoustic Plate Reformatter (Labcyte (Sunnyvale, Calif.)) And then using Thermo Fisher Combi (Thermo Fisher Scientific (Waltam, Massachusetts)). And diluted to 2x stock with assay buffer (40 μl).

Calcium flux was measured as an increase in the fluorescence static ratio using a Functional Drug Screening System (FDSS) 6000 or 7000 (Hamamatsu Corporation (Tokyo, Japan)). Compounds were applied to the cells in 2 seconds by protocol using the automated system of FDSS (20 μl, 2X) and data were collected at 1 Hz. At 143 seconds, 10 µl of the EC ₂₀ concentration of the muscarinic receptor agonist acetylcholine was added (5X), and at 268 seconds, 12 µl of the EC ₈₀ concentration of acetylcholine was added (5X). Agonist activity was analyzed as a concentration-dependent increase in calcium mobilization upon compound addition. Positive allosteric modulator activity was analyzed as a concentration dependent increase in the EC ₂₀ acetylcholine reaction. Antagonist activity was analyzed as a concentration dependent decrease in the EC ₈₀ acetylcholine reaction; For the purposes of the table herein, IC ₅₀ (inhibition concentration 50) was calculated as the concentration dependent reduction of the reaction caused by the EC ₈₀ concentration of acetylcholine. XLFit curve fitting software for Excel (Redmond, Washington) or Prism (GraphPad Software, Inc. (San Diego, CA)) (IDBS (Bridgewater, NJ)) or Dotmatics software platform (Dotmatics, Bishops Stottford, UK In)), a concentration-response curve was generated using a 4-parameter logistic equation.

The assay described above was also operated in a second mode in which an appropriate fixed concentration of the present compound was added to the cells and response in the cells was measured after establishing a fluorescence baseline for about 3 seconds. After 140 seconds, a complete concentration-response range consisting of increasing concentrations of agent was added, and a calcium response (maximum-local minimum response) was measured. EC ₅₀ values for agents with or without test compounds were determined by nonlinear curve fitting. The decrease in the EC ₅₀ value of the agonist with an increase in the concentration of the present compound (shift in the left side of the agonist concentration-response curve) is an indication of the degree of muscarinic positive allosteric regulation at a given concentration of the present compound. The increase in the EC ₅₀ value of the agonist with increasing concentration of the compound (right shift of the agonist concentration response curve) is an indication of the degree of muscarinic antagonism at a given concentration of the compound. The second mode also indicates whether the present compound also affects the maximal response of the muscarinic receptor to the agonist.

C. mAChR  M ₄  Compound activity in cell-based assays

The compound was synthesized as described above. Activity (IC ₅₀ and E _min ) was determined in a mAChR M ₄ cell based functional assay as described above, and data are listed in Tables 2 and 3. The compound numbers correspond to the compound numbers used in the Examples and Table 1 and Table 1.1.

[Table 2]

[Table 3]

7. Additional aspects of the invention and Implementation

E1. A compound of Formula I or a pharmaceutically acceptable salt thereof:

[Formula I]

(here,

A is a 5 or 6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 9 to 10 membered fused bisyl having 1 to 4 nitrogen atoms. Is a click heteroaryl ring system, wherein A is optionally substituted with 1 to 4 substituents independently selected from halo, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl;

Q is selected from NR ^a , O and CR ^b R ^c ;

R ¹ is hydrogen, halo, -OR ^d , -N (R ^d ) ₂ , C ₁ -C ₄ alkyl, -CH = CH-C ₁ -C ₄ alkyl, optionally substituted cycloalkyl, optionally substituted cyclo Alkenyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl and -CH = CH-G;

G is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycle, an optionally substituted aryl or an optionally substituted heteroaryl;

R ² and R ³ are independently selected from hydrogen, C ₁ -C ₄ alkyl and halo, or R ² and R ³ are taken together to form an oxo group;

Each R ⁴ is independently selected from halo, C ₁ -C ₄ alkyl and -OR ^e ;

R ⁵ and R ⁶ are independently selected from hydrogen, C ₁ -C ₈ alkyl and-(CR ^f R ^g ) _n -Y ¹ ;

Each Y ¹ is independently selected from an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycle, an optionally substituted aryl and an optionally substituted heteroaryl;

Each R ^a , R ^b , R ^c , R ^d , R ^e , R ^f and R ^g is independently selected from hydrogen, C ₁ -C ₄ alkyl and aryl;

m is 0, 1 or 2;

n is 0, 1 or 2).

E2. In E1,

A is a 5 or 6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S;

R ¹ is selected from hydrogen, halo, -OR ^d , C ₁ -C ₄ alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl and optionally substituted heteroaryl, or a compound thereof Pharmaceutically acceptable salts.

E3. In E1 or E2,

Q is NR ^a ;

R ^a is hydrogen or C ₁ -C ₄ alkyl, a compound or a pharmaceutically acceptable salt thereof.

E4. In E1 or E2,

Q is NR ^a ;

R ^a is hydrogen, a compound or a pharmaceutically acceptable salt thereof.

E5. In any one of E1 to E4,

R ¹ is hydrogen, halo, -CH = CH-C ₁ -C ₄ alkyl, -CH = CH-G, C ₅ -C ₈ cycloalkenyl, 4- to 8-membered monocyclic heterocyclyl, 6 to 12 membered aryl, and 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; Wherein cycloalkenyl, heterocyclyl, aryl and heteroaryl are unsubstituted, C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ Substituted with 1, 2 or 3 substituents independently selected from haloalkoxy and -NHCOR ';

G is ₁ , 2 or independently selected from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' 6 to 12 membered aryl optionally substituted with 3 substituents;

R ', in each case, is independently C ₁ -C ₄ alkyl, a compound or a pharmaceutically acceptable salt thereof.

E6. In E5,

R ¹ is hydrogen, phenyl, naphthyl, benzodioxolyl, pyrazolyl, isoxazolyl, thienyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrrolidinyl, morpholinyl, cyclophene Tenyl or -CH = CH-G, where phenyl, naphthyl, benzodioxolyl, pyrazolyl, isooxazolyl, thienyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrrolidinyl, Morpholinyl and cyclopentenyl are unsubstituted or substituted with 1, 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy and cyano ;

G is ₁ , 2 or independently selected from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' A compound or a pharmaceutically acceptable salt thereof, wherein phenyl is optionally substituted with 3 substituents, where R 'is C ₁ -C ₄ alkyl.

E7. In any one of E1 to E4,

R ¹ is selected from halo, aryl, and 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; Where aryl and heteroaryl are unsubstituted or independent from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' Substituted with 1, 2 or 3 substituents, wherein R 'is C ₁ -C ₄ alkyl, a compound or a pharmaceutically acceptable salt thereof.

E8. In E7,

R ¹ is phenyl or pyrazolyl, wherein phenyl and pyrazolyl are unsubstituted or 1, 2 independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy and cyano Or a compound substituted by 3 substituents, or a pharmaceutically acceptable salt thereof.

E9. E1 to E8,

R ² is hydrogen;

R ³ is hydrogen, a compound or a pharmaceutically acceptable salt thereof.

E10. E1 to E8,

R ² and R ³ taken together form an oxo group, a compound or a pharmaceutically acceptable salt thereof.

E11. In any one of E1 to E10,

m is 0, the compound or a pharmaceutically acceptable salt thereof.

E12. The method according to any one of E1 to E11,

R ⁵ is hydrogen, a compound or a pharmaceutically acceptable salt thereof.

E13. The method according to any one of E1 to E12,

R ⁶ is selected from C ₁ -C ₈ alkyl and-(CR ^f R ^g ) _n -Y ¹ ;

R ^f is hydrogen;

R ^g is selected from hydrogen, C ₁ -C ₄ alkyl and phenyl;

n is 0 or 1;

Y ¹ is C ₃ -C ₁₀ -cycloalkyl; C ₅ -C ₁₀ -cycloalkenyl; Phenyl; 5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; And 5 to 8 membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S; Wherein cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl are unsubstituted or substituted with one or two substituents independently selected from C ₁ -C ₄ alkyl, halo and C ₁ -C ₄ haloalkyl , Compound or a pharmaceutically acceptable salt thereof.

E14. The method according to any one of E1 to E13,

A is a 5-membered heteroaryl having 1 to 2 nitrogen atoms and optionally 1 to 2 additional heteroatoms independently selected from N, O and S, 6-membered heteroaryl having 1 to 2 nitrogen atoms, phthalazinyl , Imidazo [1,2-b] pyridazinyl or [1,2,4] triazolo [4,3-b] pyridazinyl, wherein A is halo, C ₁ -C ₄ alkyl and C _1- A compound or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from C ₄ haloalkyl.

E15. In E14,

A is thiazole-2,5-diyl, pyridazine-3,6-diyl, pyrazine-2,5-diyl, pyridine-2,5-diyl, phthalazine-1,4-diyl, imidazo [1 , 2-b] pyridazine-6-yl or [1,2,4] triazolo [4,3-b] pyridazine-6-yl, where A is halo, C ₁ -C ₄ alkyl and C ₁ A compound or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from -C ₄ haloalkyl.

E16. In any one of E1 to E13, A is

A compound, or a pharmaceutically acceptable salt thereof, selected from:

(here,

T is selected from O, S and NH;

U, V, W, X, Y and Z are independently selected from N and CH, wherein 1 to 3 of W, X, Y and Z are N).

E17. In any one of E1 to E13, A is

A compound or a pharmaceutically acceptable salt thereof.

E18. In any one of E1 to E13, A is

Phosphorus, a compound or a pharmaceutically acceptable salt thereof.

E19. The compound or pharmaceutically acceptable salt thereof according to any one of E1 to E13, wherein the compound is a compound of formula Ia:

[Formula Ia]

(here,

W, X, Y and Z are independently selected from N and CH, wherein 1 to 3 of W, X, Y and Z are N).

E20. In E19,

A compound or a pharmaceutically acceptable salt thereof, wherein one or two of W, X, Y and Z are N.

E21. The compound or pharmaceutically acceptable salt thereof according to any one of E1 to E13, wherein the compound is a compound of formula Ib:

[Formula Ib]

.

.

E22. The method according to any one of E19 to E21,

R ¹ is halo; Aryl; And 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; Where aryl and heteroaryl are unsubstituted or independent from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' Substituted with 1, 2 or 3 substituents, wherein R 'is C ₁ -C ₄ alkyl, a compound or a pharmaceutically acceptable salt thereof.

E23. The method according to any one of E19 to E22,

R ² is hydrogen;

R ³ is hydrogen, a compound or a pharmaceutically acceptable salt thereof.

E24. The method according to any one of E19 to E22,

R ² and R ³ taken together form an oxo group, a compound or a pharmaceutically acceptable salt thereof.

E25. The method according to any one of E19 to E24,

R ⁵ is hydrogen, a compound or a pharmaceutically acceptable salt thereof.

E26. The compound according to any one of E19 to E25,

R ⁶ is selected from C ₁ -C ₈ alkyl and-(CR ^f R ^g ) _n -Y ¹ ;

R ^f is hydrogen;

R ^g is selected from hydrogen, C ₁ -C ₄ alkyl and phenyl;

n is 0 or 1;

Y ¹ is C ₃ -C ₁₀ -cycloalkyl; C ₅ -C ₁₀ -cycloalkenyl; Phenyl; 5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; And 5 to 8 membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S; Wherein cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl are unsubstituted or substituted with one or two substituents independently selected from C ₁ -C ₄ alkyl, halo and C ₁ -C ₄ haloalkyl , Compound or a pharmaceutically acceptable salt thereof.

E27. In E1,

6- (2-Chloro-5-fluorophenyl) -N -[[6-[[3- (trifluoromethyl) -2-pyridyl] methyl] -6-azaspiro [2.5] octane-2- 1] methyl] pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (4-fluorophenyl) pyridazine-3-amine;

N -((6-(((1 R , 2 R , 4 S ) -7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl ) Methyl) -6- (1,3-dimethyl- 1H -pyrazol-4-yl) pyridazine-3-amine;

N- [6- (2,4-dimethylpyrazol-3-yl) pyridazin-3-yl] -6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octane-2- Carboxamide;

N- (6- (1,4-dimethyl-1 H -pyrazol-5-yl) pyridazin-3-yl) -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octane- 1-carboxamide;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (1,3-dimethylpyrazol-4-yl) pyridin-2- Amine;

6- (5-bicyclo [2.2.1] hept-2-enyl-methyl) - N - [6- (2,4- dimethyl-pyrazol-3-yl) pyridazin-3-yl] -6-aza-spiro [2.5] octane-2-carboxamide;

N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazole -4-yl) pyridazine-3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;

N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-chloro-5-fluoro Ro-phenyl) pyridazine-3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N -[[6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3- Amine;

6- (2-chloro-5-fluoro-phenyl) -N -[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N -[[6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;

N -[[6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-chloro-5-fluoro-phenyl) pyridazine-3- Amine;

6- (2-Chloro-5-fluoro-phenyl) -N -[[6- (2,2-diphenylethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3 -Amine;

6- (5-bicyclo [2.2.1] hept-2-enyl-methyl) - N - -6- azaspiro [6- (2-chloro-5-fluorophenyl) pyridazin-3-yl] - 2.5] octane-2-carboxamide;

N- [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] -6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octane-2-car Copy mid;

6-chloro- N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (1,3-dimethylpyrazole -4-yl) pyrazin-2-amine;

5- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyrazine- 2-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (1,3-dimethylpyrazol-4-yl) pyrazin-2- Amine;

6- (2-Chloro-4-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3- Amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (4-methyl-3-pyridyl) pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-fluorophenyl) pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (3-fluorophenyl) pyridazine-3-amine;

6- (2,4-difluorophenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (5-fluoro-2-methyl-phenyl) pyridazine-3- Amine;

6- (2,5-difluorophenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (5-fluoro-2-methoxy-phenyl) pyridazine-3 -Amine;

6- (3,4-difluorophenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

6- (3,5-difluorophenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-phenyl-pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2,4-dimethylpyrazol-3-yl) pyridazine-3 -Amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3,5-trimethylpyrazol-4-yl) pyridazine -3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (3,5-dimethylisooxazol-4-yl) pyridazine-3 -Amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-methylpyrazol-3-yl) pyridazine-3-amine ;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- [2-methyl-5- (trifluoromethyl) pyrazole-3 -Yl] pyridazine-3-amine;

N- [4- [6-[[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] amino] pyridazin-3-yl] phenyl] acetamide ;

6- (2-Chloro-3-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3- Amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (3-methyl-2-thienyl) pyridazine-3-amine;

2- [6-[[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] amino] pyridazin-3-yl] -4-fluoro-benzo Nitrile;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (7-isoquinolyl) pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (6-quinolyl) pyridazine-3-amine;

6- (1,3-benzodioxol-5-yl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3 -Amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-naphthyl) pyridazine-3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- [2- (trifluoromethoxy) phenyl] pyridazine-3-amine ;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- [4- (trifluoromethyl) -3-pyridyl] pyridazine -3-amine;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3 -Amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2-methylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine ;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2-methylpentyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine ;

6- (1,3-dimethylpyrazol-4-yl) -N -[(6-ethyl-6-azaspiro [2.5] octan-2-yl) methyl] pyridazine-3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[(6-propyl-6-azaspiro [2.5] octan-2-yl) methyl] pyridazine-3-amine;

N -[[6- (cyclopropylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3-amine;

N -[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3-amine;

N -[[6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3 -Amine;

N -[(6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2,2-diphenylethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6-[(3-methyl-2-pyridyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl ] Pyridazine-3-amine;

6- (1,3-dimethylpyrazol-4-yl) -N -[[6-[[3- (trifluoromethyl) -2-pyridyl] methyl] -6-azaspiro [2.5] octane- 2-yl] methyl] pyridazine-3-amine;

(R) -6- (2-chloro-5-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyri Chopped-3-amine;

(R) -6- (2-chloro-5-fluoro-phenyl) -N -[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3 -Amine;

(S) -6- (2-chloro-5-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyri Chopped-3-amine;

(S) -6- (2-chloro-5-fluoro-phenyl) -N -[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3 -Amine;

N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (2-chloro-5-fluoro Ro-phenyl) pyridin-2-amine;

5- (2-chloro-5-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridin-2-amine ;

N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (1,3-dimethylpyrazole -4-yl) pyridin-2-amine;

6- (2,4-dimethylpyrazol-3-yl) -N -[[6- (2-tetrahydrofuran-2-ylethyl) -6-azaspiro [2.5] octan-2-yl] methyl] Pyridazine-3-amine;

N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5-phenyl-thiazole-2-amine ;

N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5-phenyl-thiazol-2-amine;

5-phenyl- N -[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] thiazol-2-amine;

6- (2,4-Dimethylpyrazol-3-yl) -N -[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;

6- (3,3-difluoropyrrolidin-1-yl) -N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyri Chopped-3-amine;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2,4-dimethylpyrazol-3-yl) -N-methyl -Pyridazine-3-amine;

2-[[6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] oxymethyl] -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octane;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1-piperidyl) pyridazine-3-amine;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-morpholino-pyridazine-3-amine;

6- (4,4-difluoro-1-piperidyl) -N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-pyrrolidin-1-yl-pyridazine-3-amine;

N-[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-morpholino-pyridazine-3 -Amine;

N-[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-morpholino-pyridazine-3-amine;

N-[[6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-morpholino-pyridazine-3-amine;

6-morpholino-N-[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

6- (5-Bicyclo [2.2.1] hept-2-enylmethyl) -2-[[6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] oxymethyl] -6 -Azaspiro [2.5] octane;

2-[[6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] oxymethyl] -6- (cyclohexylmethyl) -6-azaspiro [2.5] octane;

N-[(6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl] -4- (1,3-dimethylpyrazol-4-yl) phthalazine-1-amine;

N-[[6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -4- (1,3-dimethylpyrazol-4-yl) phthalazine- 1-amine;

6- (cyclopenten-1-yl) -N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;

6-[(E) -3,3-dimethylbut-1-enyl] -N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyri Chopped-3-amine;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-[(E) -2- (p-tolyl) vinyl] pyridazine- 3-amine;

4- (1,3-dimethylpyrazol-4-yl) -N-[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] phthala Jin-1-amine;

N-[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -4- (1,3-dimethylpyrazol-4-yl) phthalazine-1-amine ;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -4- (1,3-dimethylpyrazol-4-yl) phthalazine- 1-amine;

N-[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -4- (1,3-dimethylpyrazole -4-yl) phthalazine-1-amine;

6- (2-Chloro-5-fluoro-phenyl) -N-[[6-[(3-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;

2-[[2-[[[6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] amino] methyl] -6-azaspiro [2.5] octane-6-yl] methyl] Benzonitrile;

6- (2-Chloro-5-fluoro-phenyl) -N-[[6-[(4-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N-[[6-[(2-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;

N-[(6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl] -6- (2-chloro-5-fluoro-phenyl) pyridazine-3-amine;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] imidazo [1,2-b] pyridazine-6-amine;

N-[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl]-[1,2,4] triazolo [ 4,3-b] pyridazine-6-amine;

N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl]-[1,2,4] triazolo [4,3-b] pyridazine- 6-amine;

N-[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl]-[1,2,4] triazolo [4,3-b] pyridazine-6-amine ;

(R) -6- (2-chloro-5-fluoro-phenyl) -N-[[6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl ] Pyridazine-3-amine;

(R) -6- (2-chloro-5-fluoro-phenyl) -N-[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl ] Pyridazine-3-amine;

N-(((1R) -6- (bicyclo [2.2.1] hept-5-en-2-ylmethyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (2 -Chloro-5-fluorophenyl) pyridazine-3-amine;

(R) -6- (2-chloro-5-fluorophenyl) -N-((6- (cycloheptylmethyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazine-3- Amine;

N-(((1R) -6-((7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- ( 2-chloro-5-fluorophenyl) pyridazine-3-amine;

N- [4- [6-[[(2R) -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] Acetamide;

N-[[(2R) -6-benzyl-6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-chloro-5-fluoro-phenyl) pyridazine-3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N-[[(2R) -6- (2-pyridylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;

6- (2-Chloro-5-fluoro-phenyl) -N-[[(2R) -6-[(3-methyl-2-pyridyl) methyl] -6-azaspiro [2.5] octane-2- 1] methyl] pyridazine-3-amine;

N-[[(2R) -6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-chloro-5-fluoro-phenyl) pyri Chopped-3-amine;

N- [4- [6-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methylamino] -4,5-dimethyl-pyridazin-3-yl ] Phenyl] acetamide;

N- [4- [6-[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] -4,5-dimethyl-pyridazin-3-yl] phenyl] Acetamide;

N- [4- [6-[[(2R) -6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] acetamide;

N- [4- [6-[[(2R) -6- (cycloheptylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] acetamide;

N- [4- [6-[[(2R) -6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] Acetamide;

N- [4- [6-[[(2R) -6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] Phenyl] acetamide;

N- [4- [6-[[(2R) -6-[(3-methyl-2-pyridyl) methyl] -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazine-3 -Yl] phenyl] acetamide;

N- [4- [6-[[(2R) -6-[(4-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] Phenyl] acetamide;

N- [4- [6-[[(2S) -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] Acetamide;

N- [4- [6-[[(2S) -6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] acetamide;

N- [4- [6-[[(2S) -6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] Phenyl] acetamide; Or a pharmaceutically acceptable salt thereof, or a compound or a pharmaceutically acceptable salt thereof.

E28. The compound or pharmaceutically acceptable salt thereof according to any one of E1 to E27, wherein the compound is isotopically labeled.

E29. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of E1 to E28, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

E30. A method of antagonizing mAChR M ₄ in a subject comprising administering to the subject a therapeutically effective amount of a compound of any one of E1 to E28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E29.

E31. A method of treating a disorder in a subject comprising administering to a mammal a therapeutically effective amount of a compound of any one of E1 to E28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E29, wherein the subject is mAChR Method of benefiting from the antagonism of M ₄ .

E32. The method of E31, wherein the disorder is a movement disorder.

E33. In E32, the disorders include Parkinson's disease, weakly-induced Parkinson's syndrome, dystonia, Tourette syndrome, dyskinesia, schizophrenia, cognitive deficiency associated with schizophrenia, excessive daytime sleep hyperactivity, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, A method selected from cerebral palsy and progressive supranuclear palsy.

E34. A method of treating motor symptoms in a subject, comprising administering a therapeutically effective amount of a compound of any one of E1 to E28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of E29 to a subject in need thereof. .

E35. In E34, the subject is Parkinson's disease, weakly-induced Parkinson's syndrome, dystonia, Tourette syndrome, dyskinesia, schizophrenia, cognitive deficiency associated with schizophrenia, excessive daytime sleep hyperactivity, attention deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, A method having a disorder selected from cerebral palsy and advanced supranuclear palsy.

It is understood that the foregoing detailed description and accompanying examples are illustrative only and are not to be construed as limiting the scope of the invention, defined only by the appended claims and equivalents thereof.

Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the invention, including, but not limited to, those related to the chemical structures, substituents, derivatives, intermediates, compounds, compositions, formulations or methods of use of the invention.

Claims (35)

A compound of Formula I, or a pharmaceutically acceptable salt thereof:
[Formula I]

(here,
A is a 5 or 6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S, or a 9 to 10 membered fused bisyl having 1 to 4 nitrogen atoms. Is a click heteroaryl ring system, wherein A is optionally substituted with 1 to 4 substituents independently selected from halo, C ₁ -C ₄ alkyl and C ₁ -C ₄ haloalkyl;
Q is selected from NR ^a , O and CR ^b R ^c ;
R ¹ is hydrogen, halo, -OR ^d , -N (R ^d ) ₂ , C ₁ -C ₄ alkyl, -CH = CH-C ₁ -C ₄ alkyl, optionally substituted cycloalkyl, optionally substituted cyclo Alkenyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl and -CH = CH-G;
G is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycle, an optionally substituted aryl or an optionally substituted heteroaryl;
R ² and R ³ are independently selected from hydrogen, C ₁ -C ₄ alkyl and halo, or R ² and R ³ are taken together to form an oxo group;
Each R ⁴ is independently selected from halo, C ₁ -C ₄ alkyl and -OR ^e ;
R ⁵ and R ⁶ are independently selected from hydrogen, C ₁ -C ₈ alkyl and-(CR ^f R ^g ) _n -Y ¹ ;
Each Y ¹ is independently selected from an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocycle, an optionally substituted aryl and an optionally substituted heteroaryl;
Each R ^a , R ^b , R ^c , R ^d , R ^e , R ^f and R ^g is independently selected from hydrogen, C ₁ -C ₄ alkyl and aryl;
m is 0, 1 or 2;
n is 0, 1 or 2). According to claim 1,
A is a 5 or 6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S;
R ¹ is selected from hydrogen, halo, -OR ^d , C ₁ -C ₄ alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, optionally substituted aryl and optionally substituted heteroaryl, or a compound thereof Pharmaceutically acceptable salts. According to claim 1,
Q is NR ^a ;
R ^a is hydrogen or C ₁ -C ₄ alkyl, a compound or a pharmaceutically acceptable salt thereof. According to claim 1,
Q is NR ^a ;
R ^a is hydrogen, a compound or a pharmaceutically acceptable salt thereof. According to claim 1,
R ¹ is hydrogen, halo, -CH = CH-C ₁ -C ₄ alkyl, -CH = CH-G, C ₅ -C ₈ cycloalkenyl, 4- to 8-membered monocyclic heterocyclyl, 6 to 12 membered aryl, and 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; Wherein cycloalkenyl, heterocyclyl, aryl and heteroaryl are unsubstituted, C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ Substituted with 1, 2 or 3 substituents independently selected from haloalkoxy and -NHCOR ';
G is ₁ , 2 or independently selected from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' 6 to 12 membered aryl optionally substituted with 3 substituents;
R ', in each case, is independently C ₁ -C ₄ alkyl, a compound or a pharmaceutically acceptable salt thereof. The method of claim 5,
R ¹ is hydrogen, phenyl, naphthyl, benzodioxolyl, pyrazolyl, isoxazolyl, thienyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrrolidinyl, morpholinyl, cyclophene Tenyl or -CH = CH-G, where phenyl, naphthyl, benzodioxolyl, pyrazolyl, isooxazolyl, thienyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrrolidinyl, Morpholinyl and cyclopentenyl are unsubstituted or substituted with 1, 2 or 3 substituents independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy and cyano ;
G is ₁ , 2 or independently selected from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' A compound or a pharmaceutically acceptable salt thereof, wherein phenyl is optionally substituted with 3 substituents, where R 'is C ₁ -C ₄ alkyl. According to claim 1,
R ¹ is selected from halo, aryl, and 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; Where aryl and heteroaryl are unsubstituted or independent from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' Substituted with 1, 2 or 3 substituents, wherein R 'is C ₁ -C ₄ alkyl, a compound or a pharmaceutically acceptable salt thereof. The method of claim 7,
R ¹ is phenyl or pyrazolyl, wherein phenyl and pyrazolyl are unsubstituted or 1, 2 independently selected from methyl, fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy and cyano Or a compound substituted by 3 substituents, or a pharmaceutically acceptable salt thereof. According to claim 1,
R ² is hydrogen;
R ³ is hydrogen, a compound or a pharmaceutically acceptable salt thereof. According to claim 1,
R ² and R ³ taken together form an oxo group, a compound or a pharmaceutically acceptable salt thereof. According to claim 1,
m is 0, the compound or a pharmaceutically acceptable salt thereof. According to claim 1,
R ⁵ is hydrogen, a compound or a pharmaceutically acceptable salt thereof. According to claim 1,
R ⁶ is selected from C ₁ -C ₈ alkyl and-(CR ^f R ^g ) _n -Y ¹ ;
R ^f is hydrogen;
R ^g is selected from hydrogen, C ₁ -C ₄ alkyl and phenyl;
n is 0 or 1;
Y ¹ is C ₃ -C ₁₀ -cycloalkyl; C ₅ -C ₁₀ -cycloalkenyl; Phenyl; 5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; And 5 to 8 membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S; Wherein cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl are unsubstituted or substituted with one or two substituents independently selected from C ₁ -C ₄ alkyl, halo and C ₁ -C ₄ haloalkyl , Compound or a pharmaceutically acceptable salt thereof. According to claim 1,
A is a 5-membered heteroaryl having 1 to 2 nitrogen atoms and optionally 1 to 2 additional heteroatoms independently selected from N, O and S, 6-membered heteroaryl having 1 to 2 nitrogen atoms, phthalazinyl , Imidazo [1,2-b] pyridazinyl or [1,2,4] triazolo [4,3-b] pyridazinyl, wherein A is halo, C ₁ -C ₄ alkyl and C _1- A compound or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from C ₄ haloalkyl. The method of claim 14,
A is thiazole-2,5-diyl, pyridazine-3,6-diyl, pyrazine-2,5-diyl, pyridine-2,5-diyl, phthalazine-1,4-diyl, imidazo [1 , 2-b] pyridazine-6-yl or [1,2,4] triazolo [4,3-b] pyridazine-6-yl, where A is halo, C ₁ -C ₄ alkyl and C ₁ A compound or a pharmaceutically acceptable salt thereof, optionally substituted with 1 to 4 substituents independently selected from -C ₄ haloalkyl. The method of claim 1, wherein A is

A compound, or a pharmaceutically acceptable salt thereof, selected from:
(here,
T is selected from O, S and NH;
U, V, W, X, Y and Z are independently selected from N and CH, wherein 1 to 3 of W, X, Y and Z are N). The method of claim 1, wherein A is

A compound or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein A is

Phosphorus, a compound or a pharmaceutically acceptable salt thereof. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is a compound of formula (Ia):
[Formula Ia]

(here,
W, X, Y and Z are independently selected from N and CH, wherein 1 to 3 of W, X, Y and Z are N). The method of claim 19,
A compound or a pharmaceutically acceptable salt thereof, wherein one or two of W, X, Y and Z are N. The compound of claim 1, wherein the compound is a compound of Formula Ib, or a pharmaceutically acceptable salt thereof:
[Formula Ib]

. The method of claim 19,
R ¹ is halo; Aryl; And 5-6 membered monocyclic heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; Where aryl and heteroaryl are unsubstituted or independent from C ₁ -C ₄ alkyl, halo, cyano, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy and -NHCOR ' Substituted with 1, 2 or 3 substituents, wherein R 'is C ₁ -C ₄ alkyl, a compound or a pharmaceutically acceptable salt thereof. The method of claim 19,
R ² is hydrogen;
R ³ is hydrogen, a compound or a pharmaceutically acceptable salt thereof. The method of claim 19,
R ² and R ³ taken together form an oxo group, a compound or a pharmaceutically acceptable salt thereof. The method of claim 19,
R ⁵ is hydrogen, a compound or a pharmaceutically acceptable salt thereof. The method of claim 19,
R ⁶ is selected from C ₁ -C ₈ alkyl and-(CR ^f R ^g ) _n -Y ¹ ;
R ^f is hydrogen;
R ^g is selected from hydrogen, C ₁ -C ₄ alkyl and phenyl;
n is 0 or 1;
Y ¹ is C ₃ -C ₁₀ -cycloalkyl; C ₅ -C ₁₀ -cycloalkenyl; Phenyl; 5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from N, O and S; And 5 to 8 membered heterocyclyl having 1 or 2 heteroatoms independently selected from N, O and S; Wherein cycloalkyl, cycloalkenyl, phenyl, heteroaryl and heterocyclyl are unsubstituted or substituted with one or two substituents independently selected from C ₁ -C ₄ alkyl, halo and C ₁ -C ₄ haloalkyl , Compound or a pharmaceutically acceptable salt thereof. The compound of claim 1,
6- (2-Chloro-5-fluorophenyl) -N -[[6-[[3- (trifluoromethyl) -2-pyridyl] methyl] -6-azaspiro [2.5] octane-2- 1] methyl] pyridazine-3-amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (4-fluorophenyl) pyridazine-3-amine;
N -((6-(((1 R , 2 R , 4 S ) -7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl ) Methyl) -6- (1,3-dimethyl- 1H -pyrazol-4-yl) pyridazine-3-amine;
N- [6- (2,4-dimethylpyrazol-3-yl) pyridazin-3-yl] -6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octane-2- Carboxamide;
N- (6- (1,4-dimethyl-1 H -pyrazol-5-yl) pyridazin-3-yl) -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octane- 1-carboxamide;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (1,3-dimethylpyrazol-4-yl) pyridin-2- Amine;
6- (5-bicyclo [2.2.1] hept-2-enyl-methyl) - N - [6- (2,4- dimethyl-pyrazol-3-yl) pyridazin-3-yl] -6-aza-spiro [2.5] octane-2-carboxamide;
N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazole -4-yl) pyridazine-3-amine;
6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;
N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-chloro-5-fluoro Ro-phenyl) pyridazine-3-amine;
6- (2-Chloro-5-fluoro-phenyl) -N -[[6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;
6- (2-Chloro-5-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3- Amine;
6- (2-chloro-5-fluoro-phenyl) -N -[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;
6- (2-Chloro-5-fluoro-phenyl) -N -[[6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;
N -[[6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-chloro-5-fluoro-phenyl) pyridazine-3- Amine;
6- (2-Chloro-5-fluoro-phenyl) -N -[[6- (2,2-diphenylethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3 -Amine;
6- (5-bicyclo [2.2.1] hept-2-enyl-methyl) - N - -6- azaspiro [6- (2-chloro-5-fluorophenyl) pyridazin-3-yl] - 2.5] octane-2-carboxamide;
N- [6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] -6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octane-2-car Copy mid;
6-chloro- N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;
N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (1,3-dimethylpyrazole -4-yl) pyrazin-2-amine;
5- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2,3,3-trimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyrazine- 2-amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (1,3-dimethylpyrazol-4-yl) pyrazin-2- Amine;
6- (2-Chloro-4-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3- Amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (4-methyl-3-pyridyl) pyridazine-3-amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-fluorophenyl) pyridazine-3-amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (3-fluorophenyl) pyridazine-3-amine;
6- (2,4-difluorophenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (5-fluoro-2-methyl-phenyl) pyridazine-3- Amine;
6- (2,5-difluorophenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (5-fluoro-2-methoxy-phenyl) pyridazine-3 -Amine;
6- (3,4-difluorophenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;
6- (3,5-difluorophenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-phenyl-pyridazine-3-amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2,4-dimethylpyrazol-3-yl) pyridazine-3 -Amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3,5-trimethylpyrazol-4-yl) pyridazine -3-amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (3,5-dimethylisooxazol-4-yl) pyridazine-3 -Amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-methylpyrazol-3-yl) pyridazine-3-amine ;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- [2-methyl-5- (trifluoromethyl) pyrazole-3 -Yl] pyridazine-3-amine;
N- [4- [6-[[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] amino] pyridazin-3-yl] phenyl] acetamide ;
6- (2-Chloro-3-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3- Amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (3-methyl-2-thienyl) pyridazine-3-amine;
2- [6-[[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] amino] pyridazin-3-yl] -4-fluoro-benzo Nitrile;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (7-isoquinolyl) pyridazine-3-amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (6-quinolyl) pyridazine-3-amine;
6- (1,3-benzodioxol-5-yl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3 -Amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-naphthyl) pyridazine-3-amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- [2- (trifluoromethoxy) phenyl] pyridazine-3-amine ;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- [4- (trifluoromethyl) -3-pyridyl] pyridazine -3-amine;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3 -Amine;
6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2-methylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine ;
6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2-methylpentyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine ;
6- (1,3-dimethylpyrazol-4-yl) -N -[(6-ethyl-6-azaspiro [2.5] octan-2-yl) methyl] pyridazine-3-amine;
6- (1,3-dimethylpyrazol-4-yl) -N -[(6-propyl-6-azaspiro [2.5] octan-2-yl) methyl] pyridazine-3-amine;
N -[[6- (cyclopropylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3-amine;
N -[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3-amine;
N -[[6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3 -Amine;
N -[(6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl] -6- (1,3-dimethylpyrazol-4-yl) pyridazine-3-amine;
6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (2,2-diphenylethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;
6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;
6- (1,3-dimethylpyrazol-4-yl) -N -[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;
6- (1,3-dimethylpyrazol-4-yl) -N -[[6-[(3-methyl-2-pyridyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl ] Pyridazine-3-amine;
6- (1,3-dimethylpyrazol-4-yl) -N -[[6-[[3- (trifluoromethyl) -2-pyridyl] methyl] -6-azaspiro [2.5] octane- 2-yl] methyl] pyridazine-3-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyri Chopped-3-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N -[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3 -Amine;
(S) -6- (2-chloro-5-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyri Chopped-3-amine;
(S) -6- (2-chloro-5-fluoro-phenyl) -N -[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3 -Amine;
N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (2-chloro-5-fluoro Ro-phenyl) pyridin-2-amine;
5- (2-chloro-5-fluoro-phenyl) -N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridin-2-amine ;
N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5- (1,3-dimethylpyrazole -4-yl) pyridin-2-amine;
6- (2,4-dimethylpyrazol-3-yl) -N -[[6- (2-tetrahydrofuran-2-ylethyl) -6-azaspiro [2.5] octan-2-yl] methyl] Pyridazine-3-amine;
N -[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5-phenyl-thiazole-2-amine ;
N -[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -5-phenyl-thiazol-2-amine;
5-phenyl- N -[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] thiazol-2-amine;
6- (2,4-Dimethylpyrazol-3-yl) -N -[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;
6- (3,3-difluoropyrrolidin-1-yl) -N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyri Chopped-3-amine;
N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2,4-dimethylpyrazol-3-yl) -N-methyl -Pyridazine-3-amine;
2-[[6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] oxymethyl] -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octane;
N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (1-piperidyl) pyridazine-3-amine;
N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-morpholino-pyridazine-3-amine;
6- (4,4-difluoro-1-piperidyl) -N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;
N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-pyrrolidin-1-yl-pyridazine-3-amine;
N-[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-morpholino-pyridazine-3 -Amine;
N-[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-morpholino-pyridazine-3-amine;
N-[[6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-morpholino-pyridazine-3-amine;
6-morpholino-N-[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;
6- (5-Bicyclo [2.2.1] hept-2-enylmethyl) -2-[[6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] oxymethyl] -6 -Azaspiro [2.5] octane;
2-[[6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] oxymethyl] -6- (cyclohexylmethyl) -6-azaspiro [2.5] octane;
N-[(6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl] -4- (1,3-dimethylpyrazol-4-yl) phthalazine-1-amine;
N-[[6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -4- (1,3-dimethylpyrazol-4-yl) phthalazine- 1-amine;
6- (cyclopenten-1-yl) -N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine-3-amine;
6-[(E) -3,3-dimethylbut-1-enyl] -N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyri Chopped-3-amine;
N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6-[(E) -2- (p-tolyl) vinyl] pyridazine- 3-amine;
4- (1,3-dimethylpyrazol-4-yl) -N-[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] phthala Jin-1-amine;
N-[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -4- (1,3-dimethylpyrazol-4-yl) phthalazine-1-amine ;
N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] -4- (1,3-dimethylpyrazol-4-yl) phthalazine- 1-amine;
N-[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -4- (1,3-dimethylpyrazole -4-yl) phthalazine-1-amine;
6- (2-Chloro-5-fluoro-phenyl) -N-[[6-[(3-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;
2-[[2-[[[6- (2-chloro-5-fluoro-phenyl) pyridazin-3-yl] amino] methyl] -6-azaspiro [2.5] octane-6-yl] methyl] Benzonitrile;
6- (2-Chloro-5-fluoro-phenyl) -N-[[6-[(4-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;
6- (2-Chloro-5-fluoro-phenyl) -N-[[6-[(2-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine- 3-amine;
N-[(6-benzyl-6-azaspiro [2.5] octan-2-yl) methyl] -6- (2-chloro-5-fluoro-phenyl) pyridazine-3-amine;
N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl] imidazo [1,2-b] pyridazine-6-amine;
N-[[6- (5-bicyclo [2.2.1] hept-2-enylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl]-[1,2,4] triazolo [ 4,3-b] pyridazine-6-amine;
N-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methyl]-[1,2,4] triazolo [4,3-b] pyridazine- 6-amine;
N-[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl]-[1,2,4] triazolo [4,3-b] pyridazine-6-amine ;
(R) -6- (2-chloro-5-fluoro-phenyl) -N-[[6- (tetrahydropyran-3-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl ] Pyridazine-3-amine;
(R) -6- (2-chloro-5-fluoro-phenyl) -N-[[6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl ] Pyridazine-3-amine;
N-(((1R) -6- (bicyclo [2.2.1] hept-5-en-2-ylmethyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- (2 -Chloro-5-fluorophenyl) pyridazine-3-amine;
(R) -6- (2-chloro-5-fluorophenyl) -N-((6- (cycloheptylmethyl) -6-azaspiro [2.5] octan-1-yl) methyl) pyridazine-3- Amine;
N-(((1R) -6-((7-oxabicyclo [2.2.1] heptan-2-yl) methyl) -6-azaspiro [2.5] octan-1-yl) methyl) -6- ( 2-chloro-5-fluorophenyl) pyridazine-3-amine;
N- [4- [6-[[(2R) -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] Acetamide;
N-[[(2R) -6-benzyl-6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-chloro-5-fluoro-phenyl) pyridazine-3-amine;
6- (2-Chloro-5-fluoro-phenyl) -N-[[(2R) -6- (2-pyridylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] pyridazine -3-amine;
6- (2-Chloro-5-fluoro-phenyl) -N-[[(2R) -6-[(3-methyl-2-pyridyl) methyl] -6-azaspiro [2.5] octane-2- 1] methyl] pyridazine-3-amine;
N-[[(2R) -6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methyl] -6- (2-chloro-5-fluoro-phenyl) pyri Chopped-3-amine;
N- [4- [6-[[6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methylamino] -4,5-dimethyl-pyridazin-3-yl ] Phenyl] acetamide;
N- [4- [6-[[6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] -4,5-dimethyl-pyridazin-3-yl] phenyl] Acetamide;
N- [4- [6-[[(2R) -6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] acetamide;
N- [4- [6-[[(2R) -6- (cycloheptylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] acetamide;
N- [4- [6-[[(2R) -6- (1-adamantylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] Acetamide;
N- [4- [6-[[(2R) -6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] Phenyl] acetamide;
N- [4- [6-[[(2R) -6-[(3-methyl-2-pyridyl) methyl] -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazine-3 -Yl] phenyl] acetamide;
N- [4- [6-[[(2R) -6-[(4-fluorophenyl) methyl] -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] Phenyl] acetamide;
N- [4- [6-[[(2S) -6- (3,3-dimethylbutyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] Acetamide;
N- [4- [6-[[(2S) -6- (cyclohexylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] phenyl] acetamide;
N- [4- [6-[[(2S) -6- (tetrahydropyran-4-ylmethyl) -6-azaspiro [2.5] octan-2-yl] methylamino] pyridazin-3-yl] Phenyl] acetamide; Or a pharmaceutically acceptable salt thereof, or a compound or a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein the compound is isotope labeled, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A method of antagonizing mAChR M ₄ in a subject comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof. A method of treating a disorder in a subject comprising administering to a mammal a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the subject benefits from antagonism of mAChR M ₄ . 32. The method of claim 31, wherein the disability is an exercise disorder. 33. The method of claim 32, wherein the disorder is Parkinson's disease, weakly-induced Parkinson's syndrome, dystonia, Tourette's syndrome, dyskinesia, schizophrenia, cognitive deficiency associated with schizophrenia, excessive daytime sleep hyperactivity, attention deficit hyperactivity disorder (attention) deficit hyperactivity disorder (ADHD), Huntington's disease, chorea, cerebral palsy and progressive supranuclear palsy. A method of treating motor symptoms in a subject, comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 35. The method of claim 34, wherein the subject is Parkinson's disease, weakly-induced Parkinson's syndrome, dystonia, Tourette syndrome, dyskinesia, schizophrenia, cognitive deficiency associated with schizophrenia, excessive daytime sleep hyperactivity, attention deficit hyperactivity disorder (ADHD), Huntington's disease, A method having a disorder selected from chorea, cerebral palsy and advanced supranuclear palsy.

Images